However, data on SABA use in the Gulf region are limited. Herein, we describe SABA prescription practices and clinical outcomes in patients with asthma from the Gulf cohort of the SABA use IN Asthma (SABINA) III study.The overuse of short-acting βIn this cross-sectional study conducted at 16 sites across Kuwait, Oman, and the United Arab Emirates, eligible patients (aged ≥ 12 years) with asthma were classified based on investigator-defined disease severity guided by the 2017 Global Initiative for Asthma report and by practice type, i.e., respiratory specialist or primary care physician. Data on demographics, disease characteristics, and prescribed asthma treatments, including SABA, in the 12 months prior to a single, prospective, study visit were transcribed onto electronic case report forms (eCRFs). All analyses were descriptive in nature. Continuous variables were summarized by the number of non-missing values, given as mean (standard deviation [SD]) and median (range). Categorical variables were summarized by frequency counts and percentages.2-agonist combinations and oral corticosteroid bursts were prescribed to 87.7% and 22.6% of patients, respectively.This study analyzed data from 301 patients with asthma, 54.5% of whom were treated by respiratory specialists. Most patients were female (61.8%), with a mean age of 43.9 years, and 84.4% were classified with moderate-to-severe disease, with a mean (SD) asthma duration of 14.8 (10.8) years. Asthma was partly controlled or uncontrolled in 51.2% of patients, with 41.9% experiencing ≥ 1 severe exacerbation in the 12 months preceding their study visit. Overall, 58.5% of patients were prescribed ≥ 3 SABA canisters, 19.3% were prescribed ≥ 10 canisters, and 13.3% purchased SABA over-the-counter (OTC) in the 12 months before the study visit. Most patients who purchased OTC SABA (92.5%) also received SABA prescriptions. Inhaled corticosteroid/long-acting βSABA over-prescription was highly prevalent in the Gulf region, compounded by purchases of nonprescription SABA and suboptimal asthma-related outcomes. Increased awareness among policymakers and healthcare practitioners is needed to ensure implementation of current, evidence-based, treatment recommendations to optimize asthma management in this region.NCT03857178 .The online version contains supplementary material available at 10.1186/s40733-022-00085-5. Asthma is one of the most common chronic respiratory diseases, estimated to affect 339 million people globally  and expeThe AIRGNE-Oman study reported a frequency of hospitalization and emergency room (ER) visits in the preceding 12 months of 30% and 58%, respectively .2-agonists (SABAs) have been prescribed for rapid symptomatic relief, despite their inherent lack of anti-inflammatory effects ), and median (range), and categorical variables were summarized as frequency counts and percentages.n = 136), followed by the UAE (n = 122) and Oman (n = 43). A slightly higher proportion of patients were treated by respiratory specialists than by primary care physicians .Of the 307 patients enrolled in the study, six were excluded because they had an asthma duration of less than 12 months; therefore, a total of 301 patients were included in the analysis . Nearly one-quarter of patients had received a high school education, while more than one-third had obtained a university and/or post-graduate education. In addition, most patients (95.7%) received full healthcare reimbursement, an observation that was consistent across practice types.Overall, the mean (SD) age of this study cohort was 43.9 15.3) years, with most patients aged 18–54 years (68.1%) (Table 5.3 yearsMost patients (84.4%) had investigator-classified moderate-to-severe asthma (GINA steps 3–5) and 15.6% had mild asthma (GINA steps 1–2), with a mean (SD) disease duration of 14.8 (10.8) years. The highest proportion of patients were at GINA treatment step 3 (41.5%)  were prescribed 0 SABA canisters , and all classified with mild asthma, were prescribed SABA monotherapy, with a mean (SD) of 10.2 (13.5) canisters in the 12 months before their study visit. Only one patient (0.6%) treated by a respiratory specialist and classified with mild asthma was prescribed a single canister of SABA monotherapy.Of 301 enrolled patients, only 14 patients (4.7%) were prescribed SABA monotherapy, with a mean (SD) of 8.9 (12.9) canisters in the 12 months preceding their study visit (Table n = 208) were prescribed SABA in addition to maintenance therapy, with a mean (SD) of 8.0 (10.9) canisters in the 12 months before the study visit  of patients purchased SABA OTC in the 12 months preceding the study visit, with 52.5% (n = 21) purchasing ≥ 3 SABA canisters (Table n = 40), the majority  also received SABA prescriptions. More than half of these patients (51.4%) received ≥ 3 SABA prescriptions and 13.5% received ≥ 10 SABA prescriptions.Overall, 13.3% n = 0 of patin = 27)] were prescribed ICS monotherapy, with a median (range) of 12.0  canisters in the 12 months before the study visit (Table n = 12) and 7.4% (n = 2) of patients were prescribed low-dose and high-dose ICS, respectively.Few patients , ICS/LABA combinations [47.3% (n = 303)], and budesonide inhalation suspension [10.5% (n = 67)] comprised the largest selection of anti-inflammatory, controller agents. On the other hand, the AIRGNE study revealed a nominal use of preventive ICS (5%) in patients with asthma in Oman, which was one of the lowest within the study [Most patients 87.7%) in this cohort were prescribed ICS/LABA fixed-dose combinations as maintenance therapy, which aligns with the classification of moderate-to-severe asthma in the majority of study participants (84.4%). Compared with previous studies in the GCC countries, we demonstrated a significant increase in the usage of ICS/LABA fixed-dose combinations in patients with asthma (76.8% in Kuwait and 73.1% in the UAE) . Similarur weeks . Leukotr7.7% in the study .Overall, 22.6% of patients were prescribed an OCS burst, most likely for management of a severe asthma exacerbation, as 79.4% of patients with OCS short burst prescriptions had ≥ 1 exacerbation in the 12 months before their study visit. Indeed, similar findings were reported in a 2018 study, which characterized patients with severe asthma in eight countries, including the UAE . In thatWhile the proportion of patients with well-controlled asthma in our study 48.8%) was greater than that in a previous study (29.4%) in the region , there r.8% was gThere are some limitations to this multicountry cohort study. Prescription data were used as a surrogate for actual medication use and as such provide no information on medication adherence, which potentially contributes to an under-estimation or over-estimation of SABA use. However, SABA over-prescriptions have been linked to a risk of asthma exacerbations and inadequate disease control , corroboPrimary, real-world data on SABA over-prescription in patients with asthma distributed across primary and respiratory specialist care represents contemporary asthma management practices and prescribing habits in the region. The findings from this study are particularly relevant considering the paradigm shift in asthma treatment guidelines with respect to SABA monotherapy  and emphResults from the SABINA III Gulf cluster cohort in Kuwait, Oman, and the UAE revealed that 58.5% of study participants were overprescribed SABA (≥ 3 canisters per year) in the 12 months preceding their study visit. SABA over-prescription occurred commonly, irrespective of prescriber type. The disease burden was high, with less than half of all patients achieving acceptable control, and 41.9% experiencing ≥ 1 severe asthma exacerbation in the preceding 12 months. As SABA over-prescriptions have been linked to suboptimal clinical outcomes , 24, theAdditional file 1: Supplementary Table 1. Study sites in SABINA Gulf study.


Disease prediction is crucial to treatment success. The aim of this study was to accurately and explicably predict, based on the first laboratory measurements, medications, and demographic information, the risk of death in patients with hypertensive chronic kidney disease within 1 and 3 years after admission to the Intensive Care Unit (ICU).  Patients with hypertensive chronic kidney disease who had been registered in the Medical Information Mart for Intensive Care (MIMIC-III) database of critical care medicine were set as the subject of study, which was randomly divided into a training set and a validation set in a ratio of 7 : 3. Univariate Cox regression analysis and stepwise Cox regression analysis were applied in the training set to identify the predictive factors of prognosis of patients with hypertensive chronic kidney disease in ICU, and the predictive nomogram based on Cox regression model was constructed. We internally validated the model in the training set and externally validated that in the validation model. The efficacy was assessed primarily through area under the receiver operating characteristic (ROC) curve, clinical decision curves, and calibration curves. n = 1231) and a validation set (n = 531). It was identified in the training set that insurance, albumin, alkaline phosphatase, the mean corpuscular hemoglobin concentration, mean corpuscular volume, history of coronary angiogram, hyperlipemia, medication of digoxin, acute renal failure, and history of renal surgery were the most relevant features. Taking 1 year and 3 years as the cut-off points, the AUC of participants were 0.736 and 0.744, respectively, in the internal validation and were 0.775 and 0.769, respectively, in the external validation, suggesting that the model is of favorable predictive efficacy.  A total of 1762 patients with hypertensive chronic kidney disease were finally included. During the 3-year follow-up, 667 patients (37.85%) died, with a median follow-up time of 220 days (1-1090). The data set were randomly divided into a training set ( We trained and validated a model using data from a large multicenter cohort, which has considerable predictive performance on an individual scale and could be used to improve treatment strategies. Hypertension is closely related to chronic kidney diseases (CKD). Kidney is the primary target of hypertension-induced target organ injury. Hypertension is the main cause of end-stage renal disease. It has been demonstrated that CKD, including that caused by hypertension, is a robust independent risk factor of cardiovascular adverse events and significantly affects the prognosis of patients , 2. ConvNomogram is a pictorial representation of a mathematical formula. They are commonly used tools to estimate prognosis in medicine. With the ability to generate an individual numerical probability of a clinical event by integrating diverse prognostic and determinant variables, nomograms fulfill our drive towards personalized medicine. Therefore, nomogram is an available approach for the exploration of risk factors related to the prognosis of patients with hypertensive chronic kidney disease, which is visual, and can stratify the risk more accurately so as to provide information for clinical decision , 10. It The data of this study was from the MIMIC-III database of critical care medicine. The MIMIC-III is a comprehensive data set containing demographic information, laboratory measurements, diagnosis, medication, survival, and scores of related assessments of each participant during ICU admission, which could be used for prognostic analysis.Basic information: ethnicity, gender, time of survival, living situation, and insurance/marital status2), partial pressure of oxygen (PO2), albumin (ALB), blood glucose, lactic dehydrogenase (LDH), serum magnesium ion concentration, MCH, MCHC, MCV, monocytes, neutrophil counts, platelet count, PT, red blood cell count (RBC), etc.Laboratory measurements: white blood cell count (WBC), creatinine, blood acid-based scale (pH), partial pressure of carbon dioxide . All laboratory data were the first measurements after patients' admission to ICU. The data set was randomly divided into a data set for training and a data set for validation in a ratio of 7 : 3 prior to the analysis. The training set was assigned to modeling and internal validation while the validation set to external validationVariables referring to diseases and surgical history  were arranged in accordance with the 9P < 0.05 was deemed as statistically significant).We selected the features of patients  from the data set. Two steps were taken to the full screening of all the features in order to evaluate the predictive potential of each feature (a Ezcox R (Version 1.0.2) to identify correlations between the variables and the prognosis of patients and to remove features that are statistically insignificantStep 1. Univariate Cox regression analysis was conducted using Step 2. Reserved variables after step 1 were included in stepwise Cox regression analysis for further screening to simplifying the modelSurvival R (Version 3.2.13) to predict the risk of death within 1 year and 3 years after ICU admission. After modeling, the training set and the validation set were included in the model to conduct the internal and external validation, respectively. Predicted values of the model were calculated. ROC curves, clinical decision curves, and calibration curves were plotted to verify the efficacy of the model. All statistical analyses were processed using R Version 4.1.2.Cox regression model was performed using 1762 participants with hypertensive chronic kidney disease were retained for the final analysis after removing patients with missing data or without ICU admission, of whom 1090 were male (61.86%) and 672 were female (38.14%). The overall survival time was 1110.19 ± 702.69 days, and the median survival time was 1460 days. There were 667 deaths (37.75%) during the first 3 years after diagnosis. The data set were divided into a training set and a validation set in a ratio of 7 : 3. There were 1231 patients in the training set with 765 male (62.14%) and 466 female (37.86%). The overall survival time in the training set was 1111.44 ± 702.16 days with the maximum of 3798 and the minimum of 1. There were 531 patients in the validation set with 325 male (61.21%) and 206 female 38.79%. The overall survival time was 1107.27 ± 704.57 days with the maximum of 3606 and the minimum of 1. The basic information of patients and variables are shown in The univariate Cox regression suggested that insurance, marital status, ethnicity, ALB, alkaline phosphatase (ALP), MCHC, MCV, neutrophil, PT, RBC, history of coronary angiogram, acute renal failure, hyperlipemia, history of renal surgery, and medication history of digoxin and vancomycin are the independent influence factors for the prognosis of hypertensive chronic kidney disease. Variables with statistical significance in the univariate analysis were included in the stepwise Cox regression, and the results suggested that insurance, albumin, alkaline phosphatase, MCHC, MCV, history of coronary angiogram, hyperlipemia, medication history of digoxin, acute renal failure, and history of renal surgery had stronger independent effects on the prognosis of hypertensive chronic kidney disease .P = 0.0251), alkaline phosphatase , MCHC , MCV , coronary angiogram , acute renal failure , hyperlipemia , digoxin , kidney surgery . The results showed that alkaline phosphatase, MCV, acute renal failure, and digoxin increased the mortality of patients with hypertensive chronic kidney disease, while insurance, albumin, MCHC, coronary angiogram, hyperlipemia, and kidney surgery decreased the mortality.The selected features were included in the Cox regression model for modeling , and theIn the internal validation, the area under the ROC curves (AUC) of one year and three years were 0.736 and 0.744, respectively. . In the Our study revealed that the nomographic model based on MIMIC-III could make a comparatively accurate prediction for the prognosis of patients with hypertensive chronic kidney disease who were admitted to ICU , suggesting its potent predictive efficacy.However, there is something controversial. According to the nomographic model, concomitance of hyperlipemia and history of renal surgery could result in increased survival rates, which is the opposite of what we perceived. We presumed that these two variables might be confounded by a certain variable; thus, we plotted the nomogram through a stepwise removing of variables in the Cox model, and there is no reverse in the variable directions of concomitant hyperlipemia and history of renal surgery. This could rule out the possibility of potential effects on these two variables by others. Despite the fact that multiple studies indicated that hyperlipemia increases the risk of cardiovascular diseases and pancreatitis, it is chronic and there is no evidence to support that hyperlipemia might increase the risk of death in critical patients admitted to ICU . A studyP = 0.0011). MCV is often used for diagnosis of anemia of various types in clinical practice, and most of the related studies were focusing on anemia [n = 1439) by Hsieh et al. reported that MCV was significantly and positively correlated with all-cause mortality, cardiovascular diseases-related mortality, and infection-related mortality and was independent of other factors, which was consistent with that observed in our study [P = 0.0404), while the use of digoxin could increase the mortality (P = 0.0294), which was consistent with our expectation. These two features are cardiovascular diseases-related, and cardiovascular function is crucial to the prognosis of patients in ICU. First, patients in ICU are persistent bedridden and usually receive peripherally inserted central catheters (PICC). Being bedridden could induce deep venous thrombosis (DVT) [On the other hand, we found that MCV had a significantly positive correlation with the risk of death of the study cohort (n anemia –20. Howeur study . Our resis (DVT) , while Pis (DVT) , and botis (DVT) . Hypercois (DVT) . Secondais (DVT) , 27. TheOur results demonstrated that the nomographic model could provide extra value for the prediction of the prognosis of patients with hypertensive chronic kidney disease in ICU. The predicted variables are explainable and dependable for ICU clinicians and could improve the clinical utilization to save the costs of treatment and time. Another merit of our study is that the laboratory data included in the training model were all the first measurements after the patients were admitted to ICU, which suggests that clinical practitioners can make better treatment strategies in the light of our nomographic model as soon as patients are admitted to ICU. The nomogram, different from the machine learning model, is visualizable, handy, and generally applicable. Though the machine learning model, such as the neural network and the random forests, could reveal the complicated nonlinear relation between different features, it comes with a price known as the “Black-Box” effect making it difficult for the determination of weights of the features . Our stuThough the limitation our study has, the nomographic model performed well and could optimize the clinical decision-making of clinicians in ICU. The nomogram, for instance, scored the overall unfavorable prognosis for patients with increased MCV level, then, whether clinicians should initiate the intensive treatment? According to the explanation of predicted features, they could decide to initiate or not to initiate the intensive treatment, to achieve a positive therapeutic effect.The nomographic model presented in this study could predict the risk of death in patients at the beginning of their admission to ICU. It is highly perspective, explainable, reliable, and clinically stable. The results showed that elevated MCV and ALP, acute renal failure, and medication of digoxin could increase the risk of death in ICU-admitted patients with hypertensive chronic kidney disease, while elevated ALB and MCHC, history of renal surgery, concomitance of hyperlipemia, and history of coronary angiogram could decrease the risk of death in the patients. Among these, the conclusion that concomitance of hyperlipemia could reduce the risk of death in critical patients is still controversial and remains to be further discussed.


Hypertension is a crucial risk factor for developing cardiovascular disease and reducing life expectancy. We aimed to detect DNA methylation (DNAm) variants potentially related to systolic blood pressure (SBP) and diastolic blood pressure (DBP) by conducting epigenome-wide association studies in 60 and 59 Chinese monozygotic twin pairs, respectively.comb-P approach. Inference about Causation through Examination of Familial Confounding was utilized to perform the causal inference. Ontology enrichment analysis was performed using Genomic Regions Enrichment of Annotations Tool. Candidate CpGs were quantified using Sequenom MassARRAY platform in a community population. Weighted gene co-expression network analysis (WGCNA) was conducted using gene expression data.Genome-wide DNA methylation profiling in whole blood of twins was performed using Reduced Representation Bisulfite Sequencing, yielding 551,447 raw CpGs. Association between DNAm of single CpG and blood pressure was tested by applying generalized estimation equation. Differentially methylated regions (DMRs) were identified by p < 1 × 10–4) and 8 DMRs were identified, with several DMRs within NFATC1, CADM2, IRX1, COL5A1, and LRAT. For DBP, 43 top CpGs (p < 1 × 10–4) and 12 DMRs were identified, with several DMRs within WNT3A, CNOT10, and DAB2IP. Important pathways, such as Notch signaling pathway, p53 pathway by glucose deprivation, and Wnt signaling pathway, were significantly enriched for SBP and DBP. Causal inference analysis suggested that DNAm at top CpGs within NDE1, MYH11, SRRM1P2, and SMPD4 influenced SBP, while SBP influenced DNAm at CpGs within TNK2. DNAm at top CpGs within WNT3A influenced DBP, while DBP influenced DNAm at CpGs within GNA14. Three CpGs mapped to WNT3A and one CpG mapped to COL5A1 were validated in a community population, with a hypermethylated and hypomethylated direction in hypertension cases, respectively. Gene expression analysis by WGCNA further identified some common genes and enrichment terms.The median age of twins was 52 years . For SBP, 31 top CpGs (WNT3A and COL5A1. Our findings provide new clues to the epigenetic modification underlying hypertension pathogenesis.We detect many DNAm variants that may be associated with blood pressure in whole blood, particularly the loci within The online version contains supplementary material available at 10.1186/s13148-023-01457-1. Hypertension is a chronic disease condition, and approximately 90% of the cases are considered as essential hypertension without a definitive cause. The prevalence of hypertension is 28.9%, and the rates of treatment and control of hypertension are only 35.3% and 13.4% in China. Hypertension has been a considerable risk factor for developing cardiovascular disease and reducing life expectancy and has become a huge burden on the nationwide health system [ADRB1, ATP2B1, SOX6, CHIC2, IGFBP3, and KCNK3 [As a complex phenotype, hypertension is controlled by both genetic and environmental factors through the interface of epigenetics. At present, the magnitude of genetic sources of variance in hypertension has been extensively explored. Wu et al. found that blood pressure had a moderate heritability with 0.61 for systolic blood pressure (SBP) and 0.58 for diastolic blood pressure (DBP) in Chinese population . Additiond KCNK3 –8. HowevIn recent years, increasingly strong evidence has supported the significant role of epigenetic mechanisms with altered gene expression in the increased susceptibility to diseases. Currently, a large number of epigenome-wide association studies (EWASs) have been conducted to explore the underlying association between genomic DNA methylation (DNAm) variants and complex traits, such as heart failure  and permFurthermore, the previous EWASs were most performed using samples from unrelated individuals, where the confounding effects from different genetic backgrounds were not well controlled for. Nowadays, the trait or disease-discordant twin design has been a popular and powerful tool for EWAS while controlling for individual genetic make-up , 18. In The primary materials and methods of this study were in accord with our previously published studies –22.The sample collection was carried out through the Qingdao Twin Registry , and detThis study was approved by the Regional Ethics Committee of the Qingdao CDC Institutional Review Boards. The ethical principles of the Helsinki Declaration were also followed. Prior written informed consent was achieved.We first identified potential monozygotic and dizygotic twins through sex and ABO blood types. Twins with opposite sex and/or different blood types were classified as dizygotic twins. Then, the zygosity of twins with same sex and blood types was further determined by DNA testing using 16 short tandem repeat markers , 25, 26.Blood pressure was measured in a sitting position following standard procedure using a mercurial table stand model sphygmomanometer. SBP was measured as Korotkoff phase I (appearance of sound) and DBP as Korotkoff phase V (disappearance of sound). Each subject took three repeated measurements, with at least one-minute interval. The mean value of these three measurements was calculated and used in subsequent analysis. All measurements greater than three standard deviations above or below the means were assigned as missing values.Bismark [BiSeq to smooth the methylation level [β-values less than 0.01 or more than 10 missing observations. After quality control, a total of 248,262 CpGs for SBP and 248,955 CpGs for DBP remained for subsequent analyses. The methylation β-value was transformed to M-value by applying log2 transformation.The total DNA extracted from whole blood was used in RRBS experiment. Briefly, genomic DNA was first digested to generate short fragments. Then the CpG-rich DNA fragments was bisulfite-converted. Finally, the cDNA library was obtained and sequenced. The raw methylation data covered 551,447 CpGs across the genome of each individual. We mapped the raw sequencing data to the human GRCh37 by Bismark  and thenon level . We contReFACTor method, a reference-free method to account for cell-type heterogeneity, and we used the top five components to correct for the cell-type composition effect on DNAm [Since total DNA was extracted from whole blood, different methylation profiles of distinct cell-types may lead to false discoveries . In our  on DNAm .TopHat2 [Cufflinks software [Briefly, the total mRNA was first extracted from whole blood. Subsequently, the RNA-Seq library was constructed and sequenced to obtain the sequenced data, which was then mapped to the human genome by TopHat2 . The gensoftware .M-value at each CpG and SBP or DBP was tested by using generalized estimating equation (GEE) approach through the geeglm function in R-package geepack, adjusting for age, sex, and cell-type composition. Moreover, in order to address the paired structure of the twin data, we included a vector which identified the clusters of twins within a pair into the GEE model. To correct for multiple testing, we calculated false discovery rate (FDR) [p < 1 × 10–6 as suggestive significance and 1 × 10–6 ≤ p < 1 × 10–5 as weaker-than-suggestive significance [p < 1 × 10–4 were reported as top CpGs of this EWAS [p < 0.05) were annotated to the nearest genes by using R-package biomaRt [The association between the DNAm te (FDR)  and defiificance . The CpGhis EWAS . The ide biomaRt , 37.p < 1 × 10–4), the causal relationship with blood pressure was investigated by the Inference about Causation through Examination of Familial Confounding (ICE FALCON) method which was a regression based method for causal inference in association studies using twins or family data [βself, βco-twin as well as β’self and β’co-twin were calculated, where βself was the estimation of overall correlation including the causal proportion and family confounding proportion, βco-twin estimated only the family confounding proportion of the correlation, and β’self and β’co-twin was the estimation of full model. If |βco-twin– β’co-twin| was similar to |βself – β’self|, then the association was due to family confounding; and if |βco-twin– β’co-twin| was much larger than |βself—β’self| (ratio > 1.5), then it indicated a causal effect.For the top CpGs  [slk) corrected p < 0.05.We applied the s (DMRs) . The sigp < 0.05) to the Genomic Regions Enrichment of Annotations Tool (GREAT) online to analyze the ontology enrichments [We submitted the identified CpGs (ichments . Annotath2) of 0.6 and there was a low correlation between environmental factors and DNAm , the sample size required for statistical power to exceed 80% in trait or disease-discordant twin design ranged from 22  to 63 (when ρε = 0.1) pairs, which was an immense improvement over the ordinary case–control design. Hence, we speculated that our study based on nearly 60 twin pairs would get a statistical power of about 80%.We have recently published a computer simulation study on the power of EWAS using twin design . AccordiR2M, E of our study was likely to be greater than 0.1 and close to 0.3. The heritability of SBP and DBP was about 0.60 in the same twin population as our study [h2 = 0.6 and R2M, E = 0.3, the sample size required for statistical power to exceed 80% in our twin design would range from 17 (when ρε = 0.8) to 25 (when ρε = 0.1) pairs, which were much less than 60 pairs. Hence, our study based on nearly 60 twin pairs would get an enough statistical power.We also estimated the correlation between environmental factors  and DNAm based on the top CpGs identified in this EWAS. We tested the correlation between intra-pair blood pressure difference and intra-pair DNAm difference of each top CpG in EWAS by using partial correlation analysis model, adjusting for age and sex. The median of absolute values of partial correlation coefficients was 0.34  for SBP and 0.27  for DBP  in EWAS. The mass spectra of cleavage products were collected using the MALDI-TOF mass spectrometry based on the MassARRAY System , and the spectra’s methylation ratio was generated by MassARRAY EpiTYPER software . The DNAm of CpGs between the two independent groups was compared by Wilcoxon rank-sum test. Binary logistic regression model was applied to evaluate the association of each CpG with hypertension while adjusting for BMI, triglyceride (TG), and fasting blood glucose (FBG). The p < 0.05 was set as statistically significant.We randomly recruited 118 hypertension cases and 149 health controls from the community to validate the CpGs mapped to p < 0.05 from a modified Fisher’s exact test.We conducted the weighted gene co-expression network analysis (WGCNA) , 43 to iA total of 60 twin pairs with a median value of 134.00 mmHg  for SBP and 59 twin pairs with a median value of 80.00 mmHg  for DBP were included in the methylation analysis. The median age of twins was 52 years . The other clinical indicators, i.e., BMI, serum uric acid, FBG, high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), and TG, showed statistically intra-pair correlated, indicating the co-twin design beneficial  were detected for the CpGs  located at SRRM1P2, showing weaker-than-suggestive significance (1 × 10–6 ≤ p < 1 × 10–5). All these top CpGs were located at/near 15 genes, including SRRM1P2, COL5A1, MIR1268A, NFATC1, NDE1, MYH11, SMPD4, TXNL1P1, MIR3147, PIP5K1C, TNK2, CACHD1, SLC47A1, etc.The Manhattan plot of EWAS on SBP is shown in Additional file p < 1 × 10–4 level  within PLCH2 detected as showing genome-wide significance (FDR < 0.05). Seven CpGs within SIM1, PLCH2, ATXN7L3B, and LOC646588 showed weaker-than-suggestive significance with 1 × 10–6 ≤ p < 1 × 10–5. All the top CpGs were located at/near 16 genes, and there was more than one CpG located at/near genes ATXN7L3B, DAB2IP, WNT3A, GNA14, EYS, KCNT1, LOC646588, MGEA5, PGR, PLCH2, SAE1, and SIM1.The association between DNAm of 43 top CpGs and DBP reached p < 1 × 10–3) between SBP and DBP, and these CpGs were annotated at genes CACNA1B, LARP4B, CSNK1G2, LOC646588, HES4, PPIAP45, GPX1, METRNL, ROBO3, and LINC00943.We found 21 common CpGs  with SBP and DBP are provided in Table NDE1 and MYH11, TXNL1P1, SMPD4, SRRM1P2, TNK2, and CACHD1, respectively. Out of these 9 CpGs, a causal effect of SBP to DNAm of 4 CpGs located at/near TXNL1P1 and SMPD4 was also observed.The results of causal inference on the top CpGs  at/near CADM2, LOC100507377, and DMRTA2 negatively correlated with SBP, whereas the trend of association between one DMR (H) at IRX1 and SBP was uncertain.A total of 8 DMRs were identified for SBP Table . As illuWNT3A, CNOT10, and DAB2IP.Out of the 12 DMRs identified for DBP Fig. , the metLots of important ontology enrichments potentially associated with SBP were found, such as nicotinic acetylcholine receptor signaling pathway, p53 pathway by glucose deprivation, notch signaling pathway, Hedgehog signaling pathway, and PI3 kinase pathway Table .Table 5TMany common ontology enrichments for SBP and DBP were observed, such as nicotinic acetylcholine receptor signaling pathway, p53 pathway by glucose deprivation, Notch signaling pathway, Hedgehog signaling pathway, and PI3 kinase pathway  for SBP and 2 pathways  for DBP were also enriched in our previous GWAS of blood pressure in twins .p < 0.05) mapped to COL5A1 in EWAS of SBP were quantified using the Sequenom MassARRAY platform. As shown in Additional file β = -0.439, p = 0.048) in hypertension cases, and this CpG was also regarded as top signal as in Table Eight CpGs (p < 0.05) mapped to WNT3A in EWAS of DBP, 3 were quantified using the Sequenom MassARRAY platform. As shown in Additional file WNT3A associated with DBP in a community population.Among the 5 CpGs  with a median age of 53 years (95% range 43–65), a median SBP of 126 mmHg (95% range 94–195), and a median DBP of 81 mmHg (95% range 64–100) in the analyses.r =  − 0.45, p = 0.03) and DBP . Among the genes where the top CpGs (p < 1 × 10–4) and DMRs were annotated in methylation analysis, 3 genes  for SBP and 7 genes  for DBP were also clustered in mediumpurple3 module in WGCNA.Additional file The genes in methylation analysis and genes clustered in mediumpurple3 module were involved in some common enrichment terms, such as voltage-gated calcium channel activity, NADH dehydrogenase (ubiquinone) activity, PPAR signaling pathway, and acetylcholine receptor activity  in SRRM1P2 was reported to be related to obesity [SRRM1P2 we identified. Moreover, the association between obesity and hypertension has clearly been confirmed [COL5A1 [NFATC1 (from dbGaP database), rs1449386 in CADM2 [IRX1 [NDE1 gene was involved in the signaling pathway by Rho GTPases, which could play a critical role in the pathogenesis of hypertension [MYH11 is a smooth muscle myosin in vascular smooth muscle cell (SMC) whose principal functions were contraction and regulation of blood pressure and blood flow distribution. The DNAm variation of MYH11 might influence the function of SMC and hence took part in the pathogenesis of hypertension [SMPD4 was a sphingomyelinase involved in sphingolipid metabolism pathway, and mounting evidence pointed toward that a derangement of this pathway might trigger the precursor clinical conditions of hypertension and hypertension itself [LRAT may be a critical biomarker of vitamin A deficiency in target organs and may regulate blood pressure through affecting renin angiotensin system biomarkers [TNK2 gene was involved in the oxidative damage response pathway, and it was demonstrated that inflammation and oxidative stress significantly contributed to the vascular dysfunction and renal damage associated with hypertension [TXNL1P1, PIP5K1C, MIR3147, and SLC47A1, underlining hypertension requires further investigation.In our EWAS on SBP, many genes where the top CpGs and DMRs were located, such as  obesity , and we  [COL5A1 , rs47990in CADM2 , and rs9M2 [IRX1  might plrtension . The prortension . The pron itself . It was omarkers . TNK2 gertension . HoweverDAB2IP, WNT3A, GNA14, KCNT1, PGR, PLCH2, SIM1, and CNOT10. It was previously reported that the SNPs rs35061590 and rs13290547 in DAB2IP might be associated with heart rate [WNT3A gene was a member of the WNT gene family, and Wnt signaling pathway played an emerging role in regulating blood pressure [GNA14 was involved in the regulation of insulin secretion pathway, and the relationship of insulin, insulin sensitivity, and hypertension had been clearly confirmed [Na channels (KCNT1 and KCNT2) showed a modest hypertensive phenotype [PGR was previously reported to be associated with DBP [PLCH2 was involved in the inositol phosphate metabolism pathway, and the inositol phosphate production in blood vessels differed in normotensive and spontaneously hypertensive rats [SIM1 variants with early-onset obesity in children was demonstrated [SIM1 with hypertension was currently unknown. The CNOT10 gene was probably associated with left ventricular remodeling in hypertension by bioinformatics-based analysis [ATXN7L3B, LOC646588, EYS, MGEA5, and SAE1, with hypertension had not been extensively researched, but they may also serve as candidates to be further verified.As for DBP, several interesting genes were also found, including art rate  and hencpressure . The prohenotype . The SNPwith DBP . The pronstrated , but theanalysis . Up untiNDE1 and MYH11 were involved in the Rho GTPase effectors pathway whose important role in the pathogenesis of vasospasm, hypertension, pulmonary hypertension, and heart failure had been demonstrated [TNK2 was involved in the oxidative damage response pathway that could cause vascular dysfunction and renal damage associated with hypertension [WNT3A and LOC646588. WNT3A was involved in Wnt signaling pathway whose role in regulating blood pressure had previously been reported [There is a particular challenge regarding the causal effects in observational epidemiological studies using high-dimensional omics data . Our stunstrated . TNK2 wartension . As for WNT3A and COL5A1 using Sequenom MassARRAY platform in a community population, and three CpGs mapped to WNT3A and one CpG mapped to COL5A1 were successfully validated. As additional replication, we also compared previously reported results in EWASs with ours. A list of differentially methylated genes could be replicated, especially the well-known hypertension-associated gene DAB2IP [MYH11), Wnt signaling pathway (NFATC1), and RhoA signaling pathway (PIP5K1C). For DBP, these common genes took part in Wnt signaling pathway , ubiquitin proteasome pathway (SAE1), and RNA degradation pathway (CNOT10), etc. Moreover, we also found many common enrichment terms, such as voltage-gated calcium channel activity [As additional validation, we quantified candidate CpGs mapped to e DAB2IP . We alsoactivity , NADH deactivity , PPAR siactivity , and aceactivity , for whiSeveral strengths can be noticed in our study. First, the trait or disease-discordant twin design we adopted has been revealed as a powerful tool for detecting the epigenetic variation underling complex diseases . Second,Nevertheless, the sample size of the present study was relatively limited due to the challenges of recruiting and identifying qualified twins. However, the trait or disease-discordant twin design we adopted had greater statistical power over the traditional cross-sectional or case–control design. For blood pressure with a moderate heritability, this design would allow for large sample size reductions comparing to the traditional designs. According to our previous study , this stWNT3A and COL5A1 is associated with blood pressure. Additionally, we also found evidence that blood pressure has a causal effect on peripheral blood DNAm, and vice versa. Our findings provide new clues to the epigenetic modification underlying hypertension pathogenesis.In summary, we found evidence that in peripheral blood from middle and old-aged Chinese twins, the DNAm at several loci within Additional file 1: Table S1. The results of partial correlation analysis model between intra-pair blood pressure difference and intra-pair DNA methylation difference of each top CpG in epigenome-wide association analysisAdditional file 2: Table S2. Basic characteristics of the participantsAdditional file 3: Fig. S1. Circular Manhattan plot for epigenome-wide association studies of systolic blood pressure (a) and diastolic blood pressure (b). The numbers of chromosome and the -log10 of p-values for statistical significance are shown. The dots represent the observed CpGs.Additional file 4: Table S3. Comparison between our results and other previously reported blood pressure or hypertension-associated differentially methylated genesAdditional file 5: Table S4. Common ontology enrichments by GREAT tool between systolic blood pressure and diastolic blood pressureAdditional file 6: Table S5. The results of validation analysis for the CpGs mapped to COL5A1 on systolic blood pressureAdditional file 7: Table S6. The results of validation analysis for the CpGs mapped to WNT3A on diastolic blood pressureAdditional file 8: Fig. S2. Relationships of consensus module eigengenes and external trait of blood pressure. Numbers in the table report the correlations with the p-values printed in parentheses. The table is color coded by correlation according to the color legend.Additional file 9: Table S7. Common enrichment terms for blood pressure between methylation analysis and weighted gene co-expression network analysis


Additionally, we discovered an association between short chain fatty acids and the Beck scale . The rearrangement of bacterial metabolites may be due to the patients’ use of increased dietary protein, with insufficient intake of products containing vegetable fiber adequacy 22.55 (±3.46) points). (4) Conclusions: Bariatric surgery affects the gut microbiota, which may play an important role in the development of depressive and gastrointestinal symptoms in patients after bariatric surgery. Low fiber consumption and increased levels of faecal isobutyric acid may lead to intestinal inflammation. There is a need for further research on this topic including a larger sample size.(1) Background: Depressive symptoms often appear after surgical treatment. (2) Methods: We involved 41 adults who underwent bariatric surgery a minimum of 6 months before the study and had the Beck scale ≥12. We analysed patients’ mental state, gut barrier markers, faecal short chain fatty acids, and microbiota. (3) Results: Gut microbiota composition differed significantly among patients undergoing two different types of surgery (F = 1.64,  The term microbiota-gut-brain axis refers to a network of connections involving many biological systems that enable two-way communication between intestinal microorganisms and the brain . This coBariatric surgery seems to be the optimal treatment for patients suffering from morbid obesity, allowing the patient to obtain weight reduction. It also provides metabolic effects and can provide relief from a number of diseases . Additionally, bariatric surgery may improve quality of life and extend the term of life . The mosAkkermansia, Escherichia, and Klebsiella and a decrease in the amount of Lactobacillus, Bifidobacterium or Faecalibacterium prausnitzii, and Coprococcus comes [The exact mechanisms inducing changes in the gut microbiota after certain types of bariatric procedures have not been closely examined. Factors influencing the composition of the gut microbiota after surgery include changes in the diet and nutritional status, differences in the anatomy and pH of the gastrointestinal tract, and variable gastrointestinal transit time as well as bile acid metabolism . Microbius comes .Notably, depressive symptoms decrease in the majority of patients within 6, 12, and 24 months after bariatric surgery. However, an increase in depressive and anxiety symptoms is observed after 36, 48, and 60 months .Firmicutes and increased amount of Bacteroidetes is noted, resulting in reduced SCFA production and deterioration of the intestinal barrier function [Actinobacteria, Enterobacteriaceae, and Alistipes as well as decreased amounts of Faecalibacterium were also observed. Moreover, the occurrence of Faecalibacterium is negatively correlated with the severity of depressive symptoms, while Prevotella and Klebsiella correlate positively with this phenomenon. Additionally, among patients with major depressive disorders (MDD), a decrease in the amount of Bifidobacterium and Lactobacillus is observed [Numerous studies confirm that mood is influenced by the composition of the gut microbiota . The occfunction ,14. In tobserved .The primary aims of the study were to assess the gut microbiota, SCFA, and markers of intestinal barrier integrity among patients ≥6 months after bariatric surgery who suffered from depressive symptoms. The secondary aims of the study included analysis of gastrointestinal symptoms , mental state, and diet. The tested hypothesis was that gut microbiota, its metabolites, and gut barrier integrity are associated with depressive symptoms.In the period from July 2018 to December 2020, 201 patients between 18 and 70 years of age who underwent bariatric surgery (SG or RYGB method) at least 6 months earlier completed the self-assessment questionnaire Beck scale used to preselection depressive symptoms. Patients scoring ≥12 points were treated as the occurrence of depressive symptoms and included to the study ,17,18. OBody composition analysis was performed using a Jawon Medical ioi-353 brand analyzer . Height (cm) was measured with the use of a measuring rod. The waist (cm) and hip circumferences (cm) were measured with a tape measure, and then the waist-hip ratio (WHR) was calculated .Beck’s Scale—a self-assessment questionnaire used to assess the occurrence and intensity of depressive symptoms. The total score ranges from 0 to 63 points, where the higher the score, the greater the severity of depressive symptoms. ≥12 points was considered to suggest the presence of depressive symptoms ,17,18.Hamilton Scale—the questionnaire was conducted by an experienced psychiatrist to objectively assess the severity of depressive symptoms. The study used a 21-point version, where a score of ≥7 points indicated the presence of depression ,21.Athenian Insomnia Scale—a scale consisting of 8 items assessing nighttime sleep patterns  as well as total sleep time, sleep quality, well-being, psychophysical fitness, and daytime sleepiness. Scores were assessed utilizing a total score of between 0 and 24 points, with a higher score representing a poorer quality of sleep. Score ≥6 points indicated insomnia .The mental state of patients was assessed using:The patients’ eating habits were assessed using the food frequency questionnaire (FFQ). The questionnaire was supplemented with questions about the type of bariatric surgery, weight reduction after surgery, supplementation used, and the presence of post-operative complaints . During the visit, a food consumption list for the last 72 h was also collected and analyzed using the 5D Diet program . Based on the data collected with the above tools, the International Diet Quality Index (DQI-I) was calculated, with the total score ranging from 0 to 100 points. The higher the number of points, the better the quality of the diet .Biological material  was collected from the patients and then stored at −80 °C until laboratory analyses were performed. Venous blood was collected in ethylenediaminetetraacetic acid (EDTA) tubes, centrifuged (3500 rpm for 10 min), and then the plasma and morphotic parts were separated into individual Eppendorf tubes. The feces were collected using a stool sampling kit  and then delivered by patients to the laboratory within 24 h.Fecal zonulin level was determined using an enzyme-linked immunosorbent assay (ELISA)  according to the manufacturer’s protocol. The absorbance was measured with a spectrophotometer  at 450 nm. Serum lipopolysaccharide (LPS) and occludin concentrations were determined by ELISA , and LPS binding protein (LBP) by ELISA  according to manufacturers’ protocols. In each case, the absorbance was measured with a spectrophotometer  at 450 nm.®XP machine . The DNA was amplified using the Metagenomic Library Construction Kit 16S (V3–V4) for Next Generation Sequencing , followed by sequencing using the Illumina MiSeq v3 2 × 250 bp kit .DNA isolation from stools and sequencing of the V3–V4 regions of the 16S rDNA gene were performed on the Illumina MiSeq apparatus  at the Clinical Molecular Biology Institute of the University of Kiel  according to their own protocol. DNA was isolated using microcentrifuge columns with silica membrane. The extracted DNA was purified using an Agencourt AMPureThe analysis was performed on 0.5 g of a faecal sample, which was then homogenized in 5 mL of water for 5 min. The pH was acidified to pH = 3 with 5M HCl and further samples were centrifuged for 20 min. The obtained samples were analyzed by gas chromatography with a flame ionization detector (FID). SCFA analysis included: acetic acid (C2: 0), propionic acid (C3: 0), isobutyric acid (C4: 0 i), butyric acid (C4: 0 n), isovaleric acid (C5: 0 i), and valeric acid (C5: 0 n). The analysis was performed using an Agilent Technologies 1260 System  gas chromatograph on a DB-FFAP column, 30 m × 0.53 mm × 0.5 µm. Hydrogen was supplied as carrier gas at a flow rate of 14.4 mL/min. The starting temperature was 100 °C. It was held for 0.5 min and then raised to 180 °C at a rate of 8 °C/min and held for 1 min. The temperature was then increased to 200 °C at a rate of 20 °C/min and held at 200 °C for 5 min. The fatty acids were identified by comparing their retention times with commercially available standards.The statistical analysis was performed in the R environment (version 4.0.5) , and the statement of values and the graphical presentation were made in MS Excel. The groups were characterized for quantitative variables by presenting the values of the mean, median, standard deviation, minimum and maximum value, range and standard error.Overlapping pairs of Illumina readings were analyzed using the  . The assSample size was determined for Permutational Analysis of Variance (PERMANOVA) which is used to detect the differences in microbial composition between two or more groups of individuals using the micropower R package for the weighted Jaccard distance metric. The necessary data for sample size estimation, i.e., within-group mean and standard deviation of the Jaccard distance, were determined using metagenomic gut samples from HMP (Human Microbiome Project). Based on the HMP dataset the smallest detectable effect size (ω2) assuming 80% was 0.0068 for 30 subjects per group  .RDA was performed on Hellinger-transformed relative abundance data in four rounds until the final model was specified. The procedure was as follows: The first round was an univariate analysis. In the second round the most significant variable was tested with all other variables in pairs. Two variables from the most significant model were tested with all other variables in the round three. Three variables from the most significant model were tested in all other variables in the last round (four). The final model was the last most significant model. Non-metric multidimensional scaling was carried out using Bray-Curtis distances and non-transformed relative abundance tables. The regression of factors to the NMDS ordination axes was performed using the envfit function. To identify bacteria that are associated with factor variables we performed species indicator analysis using the multipath function from the indiscpecies package. All permutation tests were performed with 100,000 permutations. The lattice (R 3.5.1) and ggplot2 packages)   were useThe mean age in the study group of 41 patients was 44.12 (±10.31) years. Even though the patients were, on average, 3 years post surgery, they still suffered from abdominal obesity. The anthropometric measurements are presented in The evaluation of the mental state of the patients showed the presence of mild depressive symptoms in most of them—the mean value of the Beck scale was 18.42 (±7.63) points. The presence of depressive symptoms was also confirmed by the Hamilton scale, the mean value of which was 12.94 (±4.7) points. Additionally, sleep disorders were reported among the studied patients through the Athenian Insomnia Scale (the result of which was 10.11 (±4) points). Detailed information is presented in The most common symptom reported by patients was problems with defecation, which affected 67.5% of participants. Additionally, 40% of patients suffered from constipation and 30% had diarrhea. Flatulence (7.5%) was the least common symptom in this group of participants. A summary of all reported complaints is presented in The analysis of endotoxemia parameters showed that the mean blood level of LBP in patients was 594.09 (±196.81) ng/mL, LPS 102.09 (±34.66) pg/mL, occludin 13.77 (±3.41) ng/mL, and faecal zonulin concentration 137.05 (±73.54) ng/mL. Detailed results of the performed laboratory tests are presented in The analysis of participants’ diet showed that the patients consumed protein consistent with postoperative recommendations . The amoThe taxonomic composition of the gut microbiota obtained from all participants was expressed in terms of operational taxonomic units (OTUs) .p = 0.00002). Also, we found an association with short-chain fatty acids ; and borderline significant association with the Beck scale . The final model was constructed after four rounds of model fitting with one, two, three, and four variables, (see Methods) and included SCFAC2, SCFAC4i, and Beck scale . As these variables were co-varying with the community composition, they could possibly cause a change in the compositional pattern of this community  was performed using Bray-Curtis distances calculated on relative abundances. To visualize the underlying trends in microbial composition, environmental variables were overlayed onto ordination plot by using regression of environmental variables on NMDS ordination scores (with envfit function). Two variables were significant: SCFAC4i ommunity . Total oommunity  . Patienommunity .To the best of our knowledge, this is the first study dedicated to investigating the relationship between the gut microbiota, the intestinal barrier markers, diet, and the occurrence of depressive symptoms among patients after surgical treatment of morbid obesity using RYGB and SG methods.Numerous studies indicate an improvement in the mental health of patients after bariatric surgeries, including improvement of the quality of life, increased self-esteem, improved body image, or a reduction in the severity of depressive symptoms and anxiety among patients ,32,33,34Bifidobacterium, Faecalibacterium, and Ruminococcus). At the same time, the authors indicated that patients with MDD had an increased number of Anaerostipes, Blautia, and Clostridium , as well as bacteria with a high ability to metabolize proteins and amino acids  [Chronic inflammation is associated with obesity. Moreover, patients with obesity are more likely to develop depression than the general population, suggesting the importance of the microbiota-gut-brain axis ,42. In aistipes) . Additioistipes)  it has bistipes) . Therefoistipes) ,46.Enterobacteriaceae  [Parasutterella  [Enterococcus . Especially E. faecalis and E. faecium are related with serious complications and nosocomial infections [Sellimonas in the feces of this group of patients is somewhat surprising. It is postulated that these bacteria can potentially have a beneficial effect on the health of the host, and S. intestinalis may serve as a biomarker of the return of homeostasis within the gut microbiota [In the studied group of patients, as many as 67.5% suffered from defecation problems, 40% experienced chronic constipation, and 30% experienced chronic diarrhea. The gut microbiota of patients suffering from gastrointestinal complaints was characterized by a significantly higher relative abundance of disease) , Parasutestines) , or Entefections . The precrobiota .Bacteroides and Clostridium) of branched-chain amino acids  [The gut microbiota associated with the occurrence of gastrointestinal complaints among the studied patients was also related to the increased concentration of isobutyric acid in the feces . This acleucine) . We stilleucine) . Additioleucine) ,53,54. Tleucine) ,56. Addileucine) . In studleucine) ,59,60,61leucine) ,63, a loleucine) .Sarcina, Butyrivibrio, Alkaliphilus, Lachnospira, Pseudoalteromonas, and Cetobacterium in relation to people who have achieved successful weight loss after surgery [In the current study, the normal BMI range was observed only in 6 patients and more than 50% of patients suffered from obesity see . Obesity surgery .This study has several limitations worth noting. Although we stated that the number of patients who met the inclusion criteria were 91, only 41 people were enrolled in this research. Different surgery methods (SG and RYGB) and the obesity of most participants can be a significant confounder factor of microbiota analysis. This undoubtedly makes it necessary to repeat the study on a larger group of participants. Secondly, it is worth remembering that BCFA in the stool is dependent on their synthesis, utilization, and absorption. In this study, we examined only BCFA level in the stool (without blood level concentration).The type of bariatric surgery affects the microbiota in different ways. Studies have suggested that the gut microbiota may play a role in the development of depressive symptoms and gastrointestinal complications in patients after bariatric surgery. Low fiber consumption and an increased level of fecal isobutyric acid may indicate increased proteolytic fermentation and lead to intestinal inflammation. There is a need for further research on this topic, including a bigger sample size.


Post-stroke dementia (PSD) has adverse effects on the quality of work and life in elderly stroke survivors. There are inconsistent results on the impacts of blood pressure control on the risk of PSD in people aged 65 years and above.This study was performed to explore whether poorly-controlled blood pressure was associated with an increasing risk of PSD.The study population was enrolled from cross-sectional research conducted in 106 communities of rural northern China. In Phase I, a total of 7,448 people aged ≥65 years, including 830 with stroke history, completed a questionnaire, a physical examination, and a cognitive assessment. Phase II further confirmed the diagnosis of PSD. Well-controlled blood pressure was defined as an average systolic blood pressure of <140 mmHg and average diastolic blood pressure of <90 mmHg over two readings in person. Failure to meet these criteria was considered as poorly-controlled blood pressure.vs.15.3%, P < 0.001), be older , and have a worse cognitive level . Compared with well-controlled blood pressure patients, poorly-controlled blood pressure in stroke survivors significantly increased risk of PSD  after adjusting for age, gender, and education.The crude prevalence rate of PSD among stroke survivors aged 65 years and over was 17.8% [95% confidence interval (CI) 15.2–20.4%]. Among the 830 stroke survivors, the proportions of PSD gradually increased with age and the crude prevalence rates for PSD were 10.2% (95% CI 5.6–14.9%), 14.8% (95% CI 10.1–19.5%), 18.8% (95% CI 14.1–23.5%), and 27.4% (95% CI 20.8–34.1%) in subjects aged 65–69, 70–74, 75–79 and ≥80 years, respectively. Participants in the poorly-controlled blood pressure group were more likely to suffer from PSD (28.4 The crude prevalence of PSD among stroke survivors aged ≥65 years was 17.8% at community level. In addition to lower education level and older age, poorly-controlled blood pressure was also an independent risk factor for PSD among the elderly, which is amenable to intervention. Therefore, it is essential to control blood pressure to reduce PSD incidence. Stroke and dementia are both common diseases in aging societies , 2. PeopThe risk of PSD overlaps with the risk of stroke and dementia. Current studies –11 reveaHigh blood pressure, which affects more than 75% of people over the age of 65 years, is the leading risk factor for stroke and many other vascular diseases . Thus, hThis study was conducted in rural Ji County in northern China between April 2019 and January 2020. Using a clustering sampling method, we selected 106 community primary health care centers from 949 villages. All individuals aged ≥65 years in each village (who had been living there for at least 5 years) were selected. Selection was based on the date of birth provided on the residence certificate. Each village had one or two fixed medical staff in the local health centers who were familiar with the health of the villagers. The study was approved by the Committee for Medical Research Ethics at Tianjin Huanhu Hospital and the Tianjin Health Bureau (ID: 2019-40).n = 158), death (n = 11), migration (n = 12), hearing loss (n = 149), aphasia (n = 18), or mental disorders (n = 15), only 7,528 completed the final interview.There were two phases in the cross-sectional, door-to-door, questionnaire-based survey. All interviewers and experts received the same training on collecting information, neuropsychological assessments, and diagnosis, and participated in a retraining course every 2 months. The total number of participants aged ≥65 years in these communities was 7,891 ; howeverIn Phase I, a centralized medical examination at the health station and an in-person survey were conducted by senior neurologists and medical staff in the local health centers.via the Mini-Mental State Examination (MMSE) and Activities of Daily Living (ADL), as well as the Clinical Dementia Rating (CDR)  . The diang (CDR) .Eligible stroke survivors could proceed to Phase II of the study on the same day. The following inclusion criteria were used: (1) age ≥65 years; (2) legally lived in the community for at least 5 years before the study registration; and (3) willingness and ability to participate according to the requirements of the study. Exclusion criteria were (1) known dementia illness history before first-ever stroke; (2) stroke within 6 months; (3) problems affecting cognitive tests, such as severe dysphasia, visual deprivation, hearing loss, and disturbance of consciousness; (4) comorbidities that potentially affect cognitive function, such as malignant neoplasm, serious liver or kidney dysfunction, connective tissue disease, and malnutrition; (5) existing mental disorders; (6) a history of alcohol or drug abuse and poisoning.The second phase was performed by an expert panel. All participants included in this phase were assessed to confirm diagnosis of PSD by obtaining a detailed medical history and performing physical and neurological examinations.Dementia was diagnosed using the Fifth Edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-V). Assessments were based on data obtained from the interviews, health examinations, previous medical records, and tests for cognitive function and functional capacity. The clinical criteria used for diagnosing PSD included a history of stroke and CT/MRI of brain, and dementia symptoms after stroke occurrence lasting for ≥ 6 months .Neurologists adjudicated incident strokes by reviewing medical records  and CT/MRI scans. As part of the routine stroke evaluation for diagnoses in China, patients underwent CT or MRI.The survey of blood pressure control was according to the China PEACE Million Persons Project . Blood pt-tests, Mann–Whitney tests, or χ2 tests as appropriate. We used multiple logistic regression to analyze the association between blood pressure control and PSD. Statistical significance was defined as P < 0.05. All data were analyzed using IBM SPSS Statistics for Windows .Demographics and participant characteristics are presented using descriptive statistics. Demographic variables and risk factors were compared between groups employing n = 395, 47.6%), to have shorter education (5.38 ± 4.34 years), habits of smoking  and drinking , and to suffer from diabetes mellitus , heart disease , and hypertension  than those without stroke .There were 7,891 participants aged ≥65 years old eligible in this study, while a total of 7,448 participants were analyzed after the investigation of Phases I and II , and 830t stroke . Additiovs. 74.51 ± 5.60 years, P < 0.001) than those without PSD. Significantly, participants with PSD had lower educational attainment  and poorer blood pressure control . In addition, the percentage of drinking in PSD was lower than without PSD . There were no differences in gender, marital status, history of smoking, diabetes mellitus, and heart disease between PSD and without PSD groups.According to the PSD diagnostic criteria, 17.8% [95% confidence interval (CI) 15.2–20.4%] of stroke survivors were diagnosed. Participants with PSD were older at interview , be older , and have a worse cognitive level . Compared with the well-controlled blood pressure group, stroke survivors aged 70–74 years (P < 0.05) and ≥80 years (P < 0.01) were more likely to suffer from dementia in the poorly-controlled blood pressure group  in a rural area of northern China, consistent with previous research results. In addition to low education level and old age, poor control of blood pressure was also an independent risk factor for dementia, which is amenable to intervention. Therefore, PSD prevalence was not low among people over 65 years old at community level, and blood pressure control is essential to reduce PSD occurrence among people aged over 65 years.Despite many studies on PSD prevalence, there has been a wide range of results. A meta-analysis by Pendlebury and Rothwell , excludiOur results showed that older age and lower educational attainment were risk factors for PSD, but there was no correlation between PSD and gender. This was similar to previous studies. Most studies showed increasing older age was associated with an increased risk of PSD. A systematic review suggested that the risk of incident dementia elevated in relation to older age especially > 80 years  and age 70–79 years  vs. age 60–69 years . AlthougHypertension is a highly prevalent condition which is an established risk factor for cardiovascular and cerebrovascular disease. In 2020, a meta-analysis  includedIn our study, after adjustments for age, gender, and education, there was an increased PSD risk in those with poorly-controlled blood pressure. Among all stroke survivors, 162 (27.2%) patients had hypertension and poor control of blood pressure, which was lower than previously reported in China , 32. HowIn addition, the relationship between other vascular risk factors and PSD, such as cholesterol level, blood glucose level, are also worth discussing. But unfortunately, our study was a screening study, no cholesterol level data was collected. Van Vliet et al.  have shoThere were some limitations in this study. First, although we made the best use of imaging evidence and medical records to identify stroke events with the help of community physicians, some important stroke characteristics  were not always available. Second, since we did not perform position emission tomography or cerebrospinal fluid examination on all participants, other types of dementia types such as Alzheimer's disease and dementia with Lewy bodies could not be completely excluded from the included PSD patients. Moreover, MMSE is a short test. Although it is commonly used in cognitive screening, the exact cognitive states according to MMSE score is not accurate enough. If we can follow up further, it will be more meaningful for the diagnosis and prognosis of PSD.We found that the crude prevalence of PSD among stroke survivors aged 65 years and over was 17.8%  in a rural area of northern China. In addition to lower education level and older age, poorly-controlled blood pressure was also an independent risk factor for PSD among the elderly, which is amenable to modification. Therefore, it is essential to control blood pressure to reduce PSD incidence. A prospective cohort to explore the relationship between blood pressure control and dementia is necessary in further research, which may contribute to the secondary prevention of dementia.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The study was approved by the Committee for Medical Research Ethics at Tianjin Huanhu Hospital and the Tianjin Health Bureau (ID: 2019-40). The patients/participants provided their written informed consent to participate in this study.HW and JG contributed to analysis and interpretation of data and wrote original manuscript. ZR reviewed and revised the manuscript. YLü, JN, XM, PC, YLi, BG, YY, YLv, ZR, SL, and X-DW did the investigation, data management of the center, and revised the manuscript. YJ designed of study, supervised the research process, and revised the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China [Grant Number 82171182], Science and Technology Project of Tianjin Municipal Health Committee [Grant Numbers ZC20121 and KJ20048], and Tianjin Key Medical Discipline  Construction Project (No. TJYXZDXK-052B).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.


Asthma education programs (AEPs) have been shown to increase quality of life and reduce emergency treatments and hospital admissions. Despite the proven benefits, only a minority of asthma patients attend such programs. To increase the number of educated patients, an online education program  for asthma patients has been developed. The present study aims to investigate the effectiveness of the eAEP in terms of asthma knowledge, asthma control and emergency treatments in general practice settings.0), after two weeks (t1), three months (t2) and six months (t3). The primary outcome is the comparison of asthma knowledge gain between intervention and control groups after completion of the eAEP (two weeks after study inclusion) and fAEP (twelve weeks after study inclusion), respectively. Secondary outcomes include asthma control, frequency of emergency treatments, patient autonomy as well as attitudes towards asthma medication.This is a cluster randomized controlled trial including 100 patients with bronchial asthma from 20 general practices in Bavaria, Germany. General practices will be randomly assigned to either the intervention or control group. Patients in the intervention group will receive access to the eAEP and instructions to complete this program within two weeks. Patients in the control group will receive usual care including a referral to face-to-face AEP (fAEP) by a certified primary care physician or a pulmonologist according to guideline recommendations. Furthermore, patients of both the intervention and control groups will be invited to a follow-up consultation in their general practice after completion of the eAEP and fAEP  to discuss any open issues. Outcomes for both groups will be assessed at baseline , The online version contains supplementary material available at 10.1186/s12890-022-02217-2. Bronchial asthma is an inflammatory respiratory disease affecting both children and adults. Symptoms are periodic and often vary over the course of day and night. Common asthma symptoms include coughing, wheezing, shortness of breath and chest tightness . In mostPatient education is a substantial part of non-drug therapy and provides knowledge and skills in order to improve patient self-management , 2. StruHowever, despite the nationwide existence of several structured patient education programs, only few patients with asthma participate in such programs , 4. AEPsDue to improved accessibility, online formats might lower the threshold for participation in education programs and thereby increase participation rates. As a consequence, an online education program  for asthma patients was developed based on the face-to-face AEP (fAEP) of the Bad Reichenhall clinic in Germany, a center for inpatient pulmonary rehabilitation. The online format allows flexible use via PC, notebook or smartphone and enables patients to acquire knowledge on asthma basics, drug therapy as well as self-management.The eAEP has already been evaluated in two proof-of-concept studies , 7. It wNonetheless, the effectiveness of the eAEP at the level of general practice on asthma knowledge as well as its effect on additional clinical outcomes remain uncertain.Moreover, asthma as a chronic disease commonly requires long-term management as well as self-management skills. As patients’ willingness and ability to engage in self-management may vary depending on multiple factors such as literacy, attitudes towards asthma and medications and desire for autonomy, patients’ individual expectations and beliefs should be highlighted . We assuprimary endpoint: after the eAEP (two weeks after study inclusion) and fAEP (twelve weeks after study inclusion), respectively.secondary endpoint: three months after the eAEP (three months after study inclusion) and fAEP (six months after study inclusion), respectively.secondary endpoint: at the end of the study (six-month follow-up).Baseline-adjusted difference in the number of correctly answered questions in the AKT  between This cluster randomized controlled trial (cRCT) aims to investigate the effectiveness of the eAEP compared to usual care in terms of 1) asthma knowledge, 2) asthma control, and 3) emergency treatments including the following endpoints:2)three months after the eAEP (three months after study inclusion) and fAEP (six months after study inclusion), respectively.at the end of the study (six-month follow-up).Baseline-adjusted difference in the total sum score obtained in the asthma control test (ACT)  between 3)Difference in frequency of emergency treatments (inpatient and outpatient treatments of asthma) between intervention and control groups at six months.Further secondary endpoints include:4)Correlation between the total sum score achieved in the autonomy preference index (API)  at the t5)Correlation between the total sum score obtained in the questionnaire on attitudes towards asthma medication at the time point baseline assessment and the change in correctly answered questions in the AKT after the eAEP and fAEP, respectively.This trial further examines the relation between asthma knowledge and 4) patient autonomy as well as 5) attitudes towards asthma medication including the following endpoints:This study will be conducted as multicentre cRCT including 100 patients with bronchial asthma from 20 general practices in Bavaria, Germany. General practices will be randomly assigned to either the intervention or control group. Therefore, patients in one practice will receive the same treatment. Cluster randomization is a common procedure in health services research in primary care in order to prevent contamination of care –13.1 and FEV1/FVC. Two weeks after study enrolment, all patients will receive the AKT by mail to complete the questionnaire again. After completion of the eAEP (three weeks after inclusion) or fAEP (twelve weeks after inclusion) patients will attend a follow-up consultation in the general practice in order to review the asthma knowledge gain as well as to discuss any open issues. In order to ensure adherence to the second appointment, all patients will be contacted via phone by an employee of the Institute of General Practice and Health Services Research at the Technical University of Munich. As part of a follow-up, patients in both groups will be contacted again by mail after three as well as six months and asked to complete a questionnaire comprising the AKT, ACT, API as well as questions on the attitude towards asthma medication. In addition, at the six-month follow-up, participants will be inquired to answer questions about emergency treatments. A detailed overview of the course of the present trial can be seen in Fig. All patients with asthma will be informed about the study and informed consent will be obtained. Patients from general practices in the intervention group will receive free access to the eAEP and will be asked to complete the eAEP within the following two weeks. Patients from general practices in the control group will receive usual care including a referral to a practice of pulmonology or a certified general practice for structured fAEP. Patients will be required to attend the fAEP within twelve weeks. As part of the baseline assessment, patients will complete a questionnaire including questions on their asthma characteristics, current medication and emergency treatments within the past six months. In addition, a structured questionnaire including the AKT, ACT and API as well as questions on patients’ attitude towards asthma medication will be handed out (further details on the questionnaires are depicted in the section ‘Measurements’). Furthermore, current lung function parameters will be extracted from patient chart or spirometry will be performed to assess lung function in terms of FEVIn this study, 20 general practices in Bavaria, Germany, will be included. Practices will be recruited by contacting GP’s of the institute’s teaching practices network and of the bavarian practice-based research network (BayFoNet). The Institute of General Practice and Family Medicine, Ludwig-Maximilians-University in Munich (LMU Munich) and the Institute of General Practice, Friedrich-Alexander University Erlangen-Nürnberg (FAU), which are also part of BayFoNet, will support recruitment of general practices. The allocation of the general practices to the intervention or control group will be conducted by a statistician (AH) of the study team, whom is not involved in the study conduct. For this purpose, a randomization sequence will be generated using the program R . The allocation ratio of intervention to control group at 1:1, no stratification, and randomly varying block sizes will be documented in advance. The randomization list will be prepared and retained by the statistician. After inclusion of general practices in the study, practices will be consecutively added to the randomization list by the statistician and assigned an appropriate sequential number. The statistician will report the corresponding classification of the practice into the study arm to the study coordinator.After allocation of the general practice to the intervention or control group, patients will be consecutively recruited by the participating general practice. Patients will not be blinded with regard to the intervention. The practice team will check the inclusion and exclusion criteria. Furthermore, the attending physician will inform patients about the study. If patients may be eligible for the study but are unwilling to participate, age, sex, and the reason for non-participation will be documented anonymously using a non-responder list. Thus, it is possible to conduct a non-responder analysis to assess acceptance of the eAEP offer as well as fAEP.Adult patients with confirmed diagnosis of bronchial asthma visiting one of the 20 participating practices will be included consecutively. All patients had been diagnosed with asthma by a pulmonologist according to defined criteria. Patients are eligible for inclusion if they have not yet attended an asthma education program or have not attended such program within the past ten years. Patients must also declare their written informed consent to participate in the study.Patients not agreeing to the studyPatients under the age of 18 years due to legal groundsPatients not having sufficient knowledge of German as the online education program is currently only available in GermanPatients whose asthma education dates back ≤ ten yearsPatients with the following criteria will be excluded:Patients’ schedule of enrolment, interventions and assessments is summarized in Figure www.asthmaselbstmanagement.de. It is intended that patients work through the eAEP independently at home using a PC or notebook. The eAEP encompasses an introductory page, four chapters including a short quiz at the end of each chapter, a final quiz after completing the courses as well as a glossary with frequently asked questions. Chapter one conveys basic knowledge on bronchial asthma as a chronic disease. Furthermore, it provides information on the structure and function of the respiratory tract. In chapter two, patients will be taught about asthma medication and its application. Chapter three is about self-management and focuses on the application of an asthma diary, an asthma action plan, as well as the peak flow measurement. The last chapter provides information on how to behave during an asthma emergency. After completing the four chapters, patients’ asthma knowledge will be tested in the final quiz and feedback on their performance for sufficient learning will be provided. If asthma patients answered fewer than 80 percent of the questions correctly, they will be advised to work through the courses again.Patients from general practices in the intervention group will receive access to the eAEP. Patients will also obtain a peak flow meter and an asthma diary from their GP in advance. The use and application of these tools is addressed in the eAEP. The eAEP consists of a webpage and is available at Patients do not enter any personal data when performing the eAEP. Furthermore, there is no documentation on how often and for how long the website was accessed. In total, two to three hours are estimated for the complete and conscientious use of the program.The eAEP is based on the structured and evaluated fAEP of the Bad Reichenhall clinic in Germany. The eAEP was developed by a pneumologist with long-time experience in patient education (KS) and a general practitioner (AS). Both developers are members of the national asthma guideline board .Three weeks after study enrolment, patients in the intervention group will attend the follow-up appointment in the general practice to ensure that the content of the eAEP had been understood correctly as well as to ensure patient safety. By using the “physician-patient-appointment” questionnaire, GPs will test patients’ asthma knowledge (see section ‘Measurements’).Patients from general practices in the control group will receive care as usual according to guideline recommendations. This encompasses either a referral to a pulmonary practice for structured fAEP or a structured fAEP in a certified general practice. Patients will be asked to attend the fAEP within twelve weeks. Furthermore, patients in the control group will also receive a peak flow meter and an asthma diary in advance.Twelve weeks after study enrolment, patients in the control group will visit the general practice again to discuss remaining questions as well as to test patients’ asthma knowledge on the basis of the “physician-patient-appointment” questionnaire. At the end of the study, patients of the control group will also receive access to the eAEP.1 and FEV1/FVC will be assessed by performing a spirometry or respective parameters will be extracted from the patient chart  as well as involvement in medical decisions (6 items) . Each itIn order to assess the attitude towards medication for bronchial asthma, eight statements on drug therapy will be evaluated by the patient, given in Table In order to record emergency treatments due to asthma attacks, patients will answer two questions. These include the number of inpatient as well as outpatient emergency treatments over the past six months.All patients will receive a questionnaire by mail two weeks after study inclusion. Patients in the intervention group will be asked to complete the AKT again after they have completed the eAEP. Patients in the control group will also receive the AKT after two weeks, even if no fAEP has been attended by this time. Thus, it will be assessed whether they have already acquired knowledge about the disease independently of a fAEP using other sources such as the internet. In addition, patients from general practice in the intervention group will be asked about their internet use in general and whether they had participated in a fAEP in addition to completing the eAEP.After completion of the eAEP as well as fAEP, essential contents of the education programs will be reviewed together with the GP using a questionnaire based on the national asthma care guideline  and fAEP (twelve weeks after study inclusion), respectively. A confirmatory hypothesis test for difference between intervention and control group is performed by a linear mixed-effects model at a two-sided 5% significance level. Based on the intention-to-treat principle, all patients will be included in analysis. The baseline value (number of correctly answered questions in the AKT at baseline), time since eAEP/fAEP, and group allocation (intervention or control group) will be used as fixed effects. Cluster effects of the general practices will be included in analyses as random intercepts. As previously mentioned, missing data for this variable will be imputed by performing a worst-case-analysis. Thereby, the average knowledge gain for drop-out patients is expected to be 0 points in the intervention group and 10 points in the control group. A comparison of the asthma knowledge gain between intervention and control group will also be made three months after completion of the eAEP (three months after study inclusion)/fAEP (six months after study inclusion) and at the end of the study (six-month follow-up). Similar calculations will be applied for the secondary outcome asthma control (difference in the achieved sum score of the ACT three months after completion of the eAEP/fAEP as well as at the six-month follow-up) (see Table The present cRCT aims to investigate the effectiveness of an online asthma education program compared to usual care in terms of asthma knowledge, asthma control and emergency treatments in primary care settings.The online character of the education program presents a promising opportunity for asthma patients to increase their asthma knowledge by virtue of providing several benefits over conventional fAEPs. Particularly, improved accessibility to information is a key advantage of digital interventions as they may be extremely appealing for patients by lowering barriers to participate primarily in terms of cost and time effectiveness –19. HoweAlthough only 60 percent of patients in the pilot trial conducted in 2019 attended this appointment, the study still showed that completion of the eAEP resulted in a great increase in asthma knowledge. Patients’ knowledge levels also remained stable after three and six months . HoweverNonetheless, a common and well-known disadvantage of cRCTs may be the differences in recruitment between intervention and control groups . In mostThe results of the cRCT may promote the implementation of an online education program for asthma patients in combination with the application of an asthma action plan and regular reviews by a physician in primary care.Additional file 1. Physician documentation at baseline assessment.Additional file 2. Questionnaire on attitudes towards asthma medication.Additional file 3. Physician documentation at physician-patient-appointment after completion of the online asthma education program and face-to-face asthma education program.


Uncontrolled blood pressure contributes a huge contribution to many hypertension-related complications and it is one of the unbeaten problems for patients taking antihypertensive drugs. The association of social support and other factors with uncontrolled blood pressure during the covid-19 pandemic is not well investigated. Therefore, this study explored the determinants of blood pressure control status during the COVID-19 pandemic among patients with hypertension who were on an antihypertensive treatment.P-value less than 0.05 was declared as statistically significant in multivariable log-binomial regression analysis.A cross-sectional study was done from March to May 2021 among adults aged 18 or more patients with hypertension for three months or more on treatment in Dessie City. An interview-administered questionnaire was done using simple random sampling from hypertension follow-up register for 380 patients with hypertension. Blood pressure measurement was taken from their arm using a stethoscope and mercury sphygmomanometer at a sitting position with 90-degree back support. Uncontrolled blood pressure was also computed either the systolic or diastolic blood pressure greater than or less than the limit of uncontrolled blood pressure with regarding the age and diabetic status of patients. The perceived social support-related questionnaire was adopted from the Multidimensional Scale of Perceived Social Support (MSPSS) -12 item checklist. It was sum-up and transformed into three categories using tertile of their computed raw scores. The adjusted prevalence ratio with a 95 percent confidence interval (CI) was used to calculate the strength of the association between uncontrolled blood pressure and independent predictors using log-binomial regression analysis. A A total of 360 study participants were included in this study. The prevalence of uncontrolled blood measures in patients with hypertension with a 95% CI was 55.8. In a multivariable analysis adjusted prevalence ratio with 95% CI for poor medication adherence 1.86, being male 1.35, secondary education 0.52, and low social support 1.24 were the predictors of uncontrolled blood pressure.Uncontrolled blood pressure for patients with hypertension on treatment is higher during the COVID-19 pandemic. Being male, poor medication adherence, educational status and low social support are factors that contribute to uncontrolled blood pressure. High blood pressure (BP) remains the leading cause of premature death globally, accounting for 10.4 million deaths per year . HoweverBlood pressure control is the main goal of hypertension treatment and follow-up . Even afUncontrolled blood pressure in hypertension is one of the modifiable diseases  and mostA cross-sectional study was done from March to May 2021 among adults aged 18 or more patients with hypertension for three months or more on treatment  in DessiThe largest sample size was obtained using a single population proportion formula from the study conducted in Southwest Ethiopia with 49.7% of uncontrolled blood pressure including an assumption of 95% level of Confidence and 5% of errors  less likely of having uncontrolled blood pressure than patients with no formal education. Patients with hypertension on treatment, who had low support were 1.24 times more likely of having uncontrolled blood pressure than those patients with hypertension with high social support , of the participants had uncontrolled blood pressure. This is in line with a cross-sectional study conducted in Southwest, Ethiopia, Korea, and Iran, , 22, 23 %, of theThe raised blood pressure level of patients with hypertension after initiating treatment may be due to many reasons. Resistant hypertension is one of the commonest characteristics of patients with failure to achieve the treatment target of patients with hypertension . It may Being male is one of the substantial factors for uncontrolled blood pressure. This is consistent with the longitudinal study conducted in Ghana  and a crMedication adherence is one of the main predictors of controlling high blood pressure for patients with hypertension. This is consistent with the study conducted in Nigeria and Gondar, Ethiopia , 15. MedEducation is a predictor of uncontrolled blood pressure levels in patients with hypertension taking their medication for three months or more. Education is inversely associated with blood pressure control. Patients with hypertension with an educational level of secondary education and above can control their blood pressure . This maSocial support is a factor that contributes to blood pressure control for patients with hypertension taking drugs for three months or more. Patients with hypertension with low social support are at higher risk of uncontrolled blood pressure than patients taking antihypertensive treatment . Low socSince this was a cross-sectional study, it had the same limitations as other cross-sectional studies. In this study the outcome and exposure variables are measured at the same time, it is relatively difficult to establish causal relationships from a cross-sectional study. Patients may be biased to social desirability bias for doctors since adherence status was measured utilizing a document review.In this study, uncontrolled blood pressure in patients with hypertension on treatment is higher during the COVID-19 pandemic. Being male, poor medication adherence, and low social support are factors that contribute to uncontrolled blood pressure. Whereas, educational status was inversely associated with the blood pressure control status of patients with hypertension.This study suggests that patients with hypertension on medication are still struggling to achieve target blood pressure control with a high level of low social support in the pandemics of COVID-19, so health care providers better screen patients for social support status, provide a coping mechanism for patients with low social support and refer patients to psychiatric clinics for additional psychological support.