Patients. The data was obtained from a total of 87 PA patients treated with esaxerenone. The treatment group comprised 33 patients who received esaxerenone as first-line therapy and 54 patients that switched from another MRA to esaxerenone. Measurements. Blood pressure (BP), plasma aldosterone concentration (PAC), plasma renin activity (PRA), serum potassium level, estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), and brain natriuretic peptide (BNP) were assessed before and after treatment with esaxerenone. Patients with overall reductions in their systolic or diastolic BP by 10 mmHg, or more, were considered responders. Unpaired t-tests of the biochemical and personal parameters between responders and nonresponders were run to find the most influencing characteristic for treatment success.  Retrospective cohort study. P=0.025, diastolic BP: P=0.096). Serum potassium levels increased, while eGFR decreased . No patients needed a dose reduction or treatment discontinuation of esaxerenone based on the serum potassium and eGFR criteria. UACR and BNP decreased insignificantly. The responders were significantly older than the nonresponders of the esaxerenone treatment (P=0.0035).  BP overall decreased after treatment with esaxerenone (systolic BP:  Esaxerenone was effective in older patients with primary aldosteronism. Primary aldosteronism (PA) accounts for 4–10% of hypertensive patients and is the most common cause of secondary hypertension . PA is cThe pathogenesis of PA has not been fully elucidated yet, however many histological and genetical findings have been reported . MultiplThe common treatment of PA is an adrenalectomy for patients with an APA, which reduces all-cause mortality better than mineralocorticoid receptor antagonist (MRA) treatment alone . AdditioEsaxerenone is an oral nonsteroidal MRA with higher MR-binding specificity than other MRA agents . It has n = 44) who had been diagnosed with PA and treated with esaxerenone at our institution, Chiba University Hospital, Japan, between May 2019 and July 2020. We obtained data before and on the next consultation day after treatment with esaxerenone . The patients were diagnosed with PA based on the following criteria: (1) plasma aldosterone concentrations (PAC) of >120 pg/mL, determined via radioimmunoassay, (2) aldosterone-to-renin ratio (ARR) of >200, and (3) at least one positive confirmatory result for any of the following tests: captopril test (ARR >200 at 60 or 90 min after loading 50 mg of captopril); physiological saline challenge test ; furosemide standing test (plasma renin activity (PRA) <2.0 ng/mL·h 2 hours after loading 40 mg of furosemide). All tests adhered to the Japan Endocrine Society guidelines [2. They received either 1.25 mg/day, 2.5 mg/day, or 5 mg/day.This retrospective study enrolled 87 consecutive patients  concomitant group or noncomitant group of antihypertensive drugs and (2) ESA as the first therapy group and the switch from another MRA group.Data were analyzed with GraphPad Prism 7, version X , and SAS version 9.4 . Data are expressed as means ± standard deviation (SD), median, and interquartile range. The normality of the distribution was confirmed with Shapiro–Wilk's test. In case of normally distributed data, the two groups were compared using an unpaired or paired The average age of the patients was 56 ± 11.9 years . The median follow-up values were 9.1 weeks. Information regarding the subtype diagnosis for all patients was as follows: out of 87 cases, 53 cases are N.D. (not determined), 14 are unilateral, and 20 are bilateral. To stabilize their blood pressure, most patients were taking calcium channel blockers (66.7%). There were 33 patients in the treatment group with esaxerenone as first-line therapy, while 55 patients switched from another MRA to esaxerenone. Detailed information on the number of patients that took an antihypertensive agent and on the daily dose of esaxerenone can be found in P=0.025 and 0.096, respectively). UACR and BNP decreased; however, there were no significant reductions during the observation period. The serum potassium levels increased, while the eGFR decreased  (Systolic BP and diastolic BP decreased after treatment with esaxerenone (ctively) . Two patP=0.025)  (P=0.0035) (P < 0.05).The blood pressure (BP) of 32 patients was measured before and after treatment, and those who had systolic or diastolic BP reductions of 10 mmHg, or more, were considered responders. Systolic BP before treatment was significantly higher in responders compared to nonresponders (P=0.025) . Changesctively) . Similarctively)  right. Nctively) . Changesctively) . The res=0.0035) . Biochem=0.0035) . Clinica=0.0035) . A subgrMRA is the recommended treatment for patients with PA who are unwilling to undergo surgery or who have contraindications for surgery . In thisConversely, the investigated biochemical parameters did not differ significantly between these two groups. Nevertheless, the observed changes of those measurements of PA patients after the treatment phase suggest an overall positive response. As such, both systolic and diastolic BP decreased in patients with PA after treatment with esaxerenone. Satoh et al. showed that significant reductions in systolic and diastolic BPs were observed from week 2 and continued through week 8 after treatment with esaxerenone for patients with PA . A signiIn our study, the serum potassium level significantly increased on average, and the effect of aldosterone was considered suppressed. Hyperkalemia with a serum potassium level of >5.0 mEq/L was observed in two cases; however, they were transient. Ito et al. reported that a serum potassium level of ≥5.5 mEq/L was observed in 12.1% of the patients with moderate kidney dysfunction receiving add-on treatment with esaxerenone. All increments in serum potassium levels were transient, and no patients met predefined serum potassium criteria for dose reduction or treatment discontinuation . FurtherUACR and BNP values decreased in our study; however, there were no significant reductions. This result is not surprising. Adding esaxerenone to the existing renin-angiotensin system inhibitor therapy in patients with type 2 diabetes and microalbuminuria has shown to increase the likelihood of the normalization of the albumin levels and reduced progression of albuminuria . In thisWhile the biochemical parameters suggest the esaxerenone treatment is suitable as such for the chosen type of PA patients, the only prominent factor that determined an excellent response to the treatment was age. Older patients showed significantly better response than younger patients. Consistent with our findings, greater hypotensive effects were observed in older adults (>65 years old) by subgroup analyses on previous clinical trials of esaxerenone for the patients with EHT in the Japanese population . HoweverWe also studied blood pressure in longer-term treatment with esaxerenone . Nevertheless, SBP and DBP were significantly lower in responders than in nonresponders at 1–3 months. These results suggest that the high proportion of elderly patients in the responder group was not due to the short observation period. Also, according to clinical data of nonresponders and responders, and subtype diagnosis, there seemed to be no apparent difference in the proportion of subtype diagnoses between the two groups. In this cohort, there are many patients that switched from other MRAs, and some comparisons did not have significant differences, especially in the switching group, due to the smaller sample size. In contrast, the mean results show a trend similar to that seen in the whole group.Retrospective studies are generally limited in the sense that the data have already been collected and the study design cannot be adjusted anymore in retrospective. Hence, we were limited by the relatively small sample size and short observational period. Finally, there was no washout period for other MRAs administered as pretreatment. Nonetheless, the strength of our study is that it led to candidate predictors of effectiveness regarding the treatment with esaxerenone in patients with PA.We found that U-ACR and BNP decreased after treatment with esaxerenone. Further, esaxerenone was more effective in older patients with PA.


Arterial stiffness, glycemic control and blood pressure are risk factors of macrovascular complications in type 2 diabetes. This study aimed to investigate the combined association of arterial stiffness, glycemic control and hypertension status with the occurrence of diabetic macrovascular complication.A total of 1870 patients of diabetes were enrolled from Beijing Health Management Cohort between 2008 and 2018 as baseline, and then followed for macrovascular complication onset. We proposed a composite risk score (0–4) by arterial stiffness severity, pool glycemic control and hypertension status. Cox model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI).The mean age (SD) of this population was 59.90 (12.29) years. During a median follow-up of 4.0 years, 359 (19.2%) patients developed macrovascular complication. Compared to the normal arterial stiffness and good glycemic control group, patients with severe arterial stiffness and pool glycemic control had the highest risk of macrovascular complications . Similarly, those of severe arterial stiffness and hypertension had the highest risk . Patients of the composite score > 2 had a significantly increased risk of macrovascular complication.This study suggested the clinical importance of combined evaluation of arterial stiffness, glycemic control and hypertension status for the risk stratification and management of macrovascular complication of type 2 diabetes.The online version contains supplementary material available at 10.1186/s12933-022-01696-1. Type 2 diabetes is a serious public health issue worldwide with high morbidity and mortality . DiabetePatients with diabetes had increased arterial stiffness level  and highTherefore, this study aimed to evaluate the combined association of arterial stiffness, glycemic control and hypertension status with the occurrence of diabetic macrovascular complication. We hypothesized that the combined assessment of arterial stiffness, glycemic control and hypertension status could improve the risk stratification and prediction of macrovascular complications in type 2 diabetes.We recruited participants from the Beijing Health Management Cohort (BHMC), which is an open, dynamic and population-based cohort conducted in Beijing, China. BHMC aims to collect and investigate the biomarkers of cardiometabolic diseases including diabetes and its complications. Details of the cohort design have been described in a previous study .The original cohort included 10,632 participants with physical and arterial examinations between 2008 and 2018. Then, participants without type 2 diabetes or with type 1 diabetes (n = 7495) or lacking eligible arterial stiffness data (n = 1038) were excluded at baseline. We further excluded participants with a history of macrovascular complication (n = 126), diabetic nephropathy or retinopathy (n = 71) or missing fasting glucose data (n = 32) at baseline. Finally, a total of 1 870 participants was included and followed until the development of macrovascular complication or December 31 of 2019, which came first , and health-related data (diagnosis history of diseases and medication use) were collected using a standardized questionnaire. Smoking status and drinking status were categorized into "current" and "not current". Physical activity was defined as participating in moderate or intense exercise "≥ 20 min per time and ≥ 4 times per week". Self-reported health conditions included a physician-diagnosed history of cardiovascular diseases, diabetes, hypertension, and dyslipidemia. The use of antidiabetic, antihypertensive, and lipid-lowering medications were collected.2 (m)2. Obesity was defined as BMI ≥ 28 kg/m2 In Chinese adults . Differences were compared using Student's t-test or ANOVA for variables with normal distributions, and Mann–Whitney U test or Kruskal–Wallis test for skewed variables. Categorical variables were described as numbers (proportions) and compared using χWe used two approaches to investigate the combined effect of arterial stiffness, glycemic control and hypertension status. Approach 1: the combined effect of arterial stiffness and glycemic control (or hypertension status) was evaluated separately; approach 2: we created two cumulative or weighted scores combining arterial stiffness, glycemic control and hypertension status. The detailed information was shown in Additional file Survival curves were used to present the cumulative hazard of diabetic macrovascular complications and compared by log-rank tests. Cox frailty models corrected for individual random intercept were used to compare the risk of macrovascular complication between groups. Hazard ratio (HR) with 95% confidence interval (CI) were calculated. We adjusted potential confounders in regression analyses: model 1 was adjusted for age and sex; model 2 was further adjusted for obesity, eGFR, LDL cholesterol, hypertension (if not stratified), glycemic control (if not stratified), current smoking, and physical activity. To visualize the dose–response relationship between baseline baPWV and incident macrovascular complication stratified by glycemic control and hypertension status, we carried out restricted cubic spline analysis using three knots at the 10th, 50th, and 90th percentiles.Multiple sensitivity analyses were performed to test the robustness of the results. First, 62 of 1870 participants had missing data of BMI, and then the main analysis was repeated after completing the multiple imputation using Markov Chain Monte Carlo. Second, poor glycemic control was alternatively defined as fasting glucose ≥ 5.6 mmol/L and hypertension was alternatively defined as SBP ≥ 130 mmHg or DBP ≥ 80 mmHg or use of any antihypertensive medication or self-reported diagnosis history of hypertension. All statistical analyses were performed using R software (version 4.1.1), and a two-sided significance level of P value < 0.05 was considered statistically significant.A total of 1 870 individuals with diabetes were included in this study, and 1227 (81.2%) were men. The mean age (SD) of the population was 59.90 (12.29) years. During a median follow-up of 4.0 years, 359 (19.2%) patients developed macrovascular complication. Table Figure Compared with the good glycemic control/normal arterial stiffness group, participants of poor glycemic control/severe arterial stiffness had the highest risk of macrovascular complication . The adjusted HR for good glycemic control/severe arterial stiffness group was 2.24 (95% CI: 1.17–4.30); and 1.98 (95% CI: 1.08–3.61) for poor glycemic control/moderate arterial stiffness group. No significant association was found for the poor glycemic control/normal arterial stiffness and good glycemic control/moderate arterial stiffness groups  of the population had measurements of HbA1c. Fasting blood glucose was used as a measure of glycemic control. Second, we used baPWV as the index of arterial stiffness instead of carotid-femoral pulse wave velocity (cfPWV). We can not compare the difference between these two indices. Nevertheless, studies have confirmed that baPWV correlates closely with cfPWV and has been recommended for assessing arterial stiffness by American Heart Association (AHA). Of note, there are novel techniques to estimate the arterial stiffness in addition to tonometry-derived measures, such as Doppler-derived aortic arch PWV (aa-PWV), which need investigation in further research among diabetic population . Third, In summary, this longitudinal cohort study indicated that the combined evaluation of arterial stiffness, glycemic control and hypertension status could improve the risk stratification of macrovascular complication among diabetic population, which provided novel insights into the preventive strategies against macrovascular complication from the perspective of combined intervention of arterial function and glucose metabolism.Additional file 1. Additional Methods. Table S1. Baseline characteristics of participants according to different arterial stiffness and glycemic control status. Table S2. Baseline characteristics of participants according to different arterial stiffness and hypertension status. Table S3. Association of separate arterial stiffness, glycemic control and hypertension status with the development of macrovascular complication. Table S4. Association of arterial stiffness and glycemic control/hypertension status with macrovascular complications adjusting blood pressure and fasting glucose as continuous variables. Table S5. Association of arterial stiffness and alternatively defined glycemic control status with macrovascular complications. Table S6. Association of arterial stiffness and alternatively defined hypertension status with macrovascular complications. Table S7. Association of per-SD increase of baPWV with diabetic macrovascular complication stratified by glycemic control and hypertension. Table S8. The composition of arterial stiffness, glycemic control and hypertension in each scored population. Table S9. Association of weighted score with diabetic macrovascular complications. Figure S1. Flowchart of this current study. Figure S2. Association of arterial stiffness, glycemic control and hypertension status with development of macrovascular complication in imputed data.


Several retrospective studies have identified risk factors associated with ocular myasthenia gravis (OMG) generalization in non-surgical patients. However, the outcomes of OMG after thymectomy have not been investigated fully. This study aimed to explore the clinical predictors of post-thymectomy OMG prognosis.We performed a retrospective review of OMG patients who underwent thymectomy at our institution from January 2012 to December 2021. Kaplan–Meier and Cox proportional hazard regression analyses were used to evaluate associations between clinical features and prognosis. The main outcome measures were OMG conversion, complete stable remission (CSR), and clinical improvement.P = 0.002). Patients with histotype B2/B3 thymoma showed a higher risk of conversion (P = 0.002) than did patients with hyperplasia and AB/B1 thymoma. Fifty-two patients fulfilled the criteria for CSR and improvement. Sixteen (30.8%) achieved CSR at a median time of 28.7 (15–54) months after thymectomy. Fifteen (28.8%) showed clinical improvement at last follow up. Patients who achieved CSR showed a younger age of onset (P = 0.022), lower percentage of acetylcholine receptor antibody-seropositivity (P = 0.029). Histologically, patients with thymic hyperplasia and stage I thymoma showed a higher chance of CSR (P = 0.010) than did patients with stage II/III thymoma. Multivariate analysis revealed that RNS-positivity  and histotype B2/B3 thymoma  were associated with OMG conversion. Thymic hyperplasia and stage I thymoma  were associated with OMG CSR after thymectomy.Fifty-eight patients were identified for conversion analysis. Thirteen (22.4%) developed generalized myasthenia gravis (GMG) at a median time of 12.7 (3–37.3) months from symptom onset. Repetitive nerve stimulation (RNS)-positivity was associated with increased risk of conversion to GMG (For OMG patients after thymectomy, RNS-positivity and histotype B2/B3 thymoma are independent predictors of conversion to GMG. On the other hand, thymic hyperplasia and stage I thymoma independently predict CSR. Myasthenia gravis (MG) is an autoimmune disease caused by pathogenic autoantibodies to components of the postsynaptic muscle endplate. The typical manifestation is fluctuations in severity of muscle weakness . AccordiPatients with pure OMG and SGMG can differ significantly in the clinical course and impairment of daily life. Several retrospective studies have identified certain risk factors associated with OMG conversion, which include sex, older age of onset , antibodIn view of the rarity of studies on surgery in OMG, this study aimed to address two issues pertinent to OMG patients post-thymectomy: we sought to report on long-term post-thymectomy OMG prognosis and to explore factors affecting post-thymectomy OMG outcomes.We conducted a retrospective study of 82 consecutive OMG patients who underwent thymectomy at Tianjin Medical University General Hospital from January 2012 to December 2021. The diagnosis of OMG was based on typical clinical manifestations, consisting of fluctuating diplopia, ptosis, or both, and at least one positive result in the following tests: (1) Anti-AChR Ab, (2) RNS, or (3) clinical response to edrophonium chloride (Tensilon test) or pyridostigmine.Outcome measures consisted of development of GMG, complete stable remission (CSR) and clinical improvement, time to OMG conversion  and to CSR .Inclusion criteria were an onset age ≥ 18 years, a minimum of 3 months of isolated ocular disease, R0 resection for thymoma, and follow-up duration of at least 2 years: 2 years or more from symptom onset or until GMG developed in conversion analysis, and 2 years or more after thymectomy for CSR and clinical improvement analysis. Patients who were lost to follow-up or who had incomplete clinical data were excluded from this study. We also excluded patients with thymic carcinomas or cysts because these conditions have not been validated to be associated with MG pathogenesis .GMG was defined by any symptoms beyond the extraocular muscles or eyelid, including dysphagia, dysarthria, dyspnoea, dysphonia, neck or extremity weakness, with the above positive serological or physiological testing. CSR was defined as the absence of any symptoms or signs of MG for at least 1 year without any medication for MG. Clinical improvement was defined as a substantial decrease in pre-treatment clinical manifestations or a sustained substantial reduction in MG medications.Extended thymectomy, defined as resection of the entire thymus and mediastinal fat tissue between both phrenic nerves, was performed for all patients. Indications for thymectomy included thymic abnormality suggestive of thymoma on diagnostic imaging, or in suspicion of hyperplasia but with inadequate response to acetylcholinesterases, resistance to taking immunosuppressive (IS) therapy or with contraindications to or being refractory to IS agents. With respect to OMG patients in whom it was difficult to differentiate thymoma from thymic hyperplasia in thymic imaging, we still recommended thymectomy, to eliminate any possible thymoma. For patients with a high suspicion of thymic hyperplasia, it was recommended that they make their own decision regarding surgery, after a comprehensive explanation of the pros and cons of both medical treatment and surgery.This study was approved by the ethics committee of Tianjin Medical University General Hospital  and was conducted according to the principles of the Declaration of Helsinki. The need for obtaining patient consent was waived due to the nature of the study.After inclusion and exclusion criteria screening, twenty-four patients were excluded from the study. Therefore, a total of 58 patients were finally identified for OMG conversion study, 52 patients were eligible for CSR analysis. The flowchart of recruitment and exclusion detail was shown in Fig. The following variables that may predict conversion and CSR were evaluated: age, sex, clinical symptoms at onset , anti-AChR Ab statis, RNS status, thymus histology, Masaoka–Koga Stage of thymoma, tumour location, tumour size, surgical approach, duration of symptoms before surgery, and immunosuppressive treatment  after surgery.Thymoma histology was classified according to the WHO criteria  by localThe tumour location and size were determined from preoperative thoracic imaging examinations. If the tumour boundary exceeded the left/right sternal border, it was defined as left or right thymoma, respectively. Both maximum and mean tumour diameter  were evaluated.Both AchR and MuSK Abs were tested in all patients. The presence of AChR Abs was considered positive with the titre > 0.5 nmol/L, and the presence of MuSK Ab was considered when the titre > 0.01 nmol/L, as assessed in radioimmune assays.The RNS test was routinely conducted in the bilateral orbicularis oculi muscle for OMG. A decrement of more than 10% with 3-Hz stimulation was considered to represent a positive result.Pyridostigmine alone or in combination with prednisone were prescribed by neurologists, according to OMG symptoms before surgery Generally, prednisone was recommended for patients with diplopia. After symptomatic control was achieved, the dose was tapered over months to the minimum effective dose or withdrawal. When corticosteroids were ineffective, or when side effects limited their use, or when contraindications precluded their use entirely, additional immunosuppressive agents, such as tacrolimus, azathioprine, mycophenolate mofetil, or methotrexate were considered.t-tests. Cumulative incidence of OMG conversion and CSR were analysed using the Kaplan–Meier method and the log-rank test. Univariate and multivariate Cox proportional hazards regression analysis was applied to determine the factors affecting OMG conversion and CSR during the follow-up period. A P value < 0.05 was considered statistically significant. All data analyses were performed using SPSS Statistics for Mac version 25.0 .Categorical variables were analysed using the chi-square and Fisher’s exact test. Continuous variables were analysed with two-tailed P = 0.085), although no statistically significant difference was reached. RNS-positivity was associated with an increased risk of conversion to GMG, with 84.6% of those with RNS-positivity converting to GMG, as compared with 35.6% of patients who were RNS-negative (P = 0.002). We did not find a difference in conversion rate between OMG with thymoma and hyperplasia  compared to the group of patients with either hyperplasia or subtype AB/B1 thymoma.The median follow-up duration after thymectomy in our 58 OMG patients was 59.3 range 9–114.5) months. At last review, 13 (22.4%) patients had developed GMG at a median conversion time of 9.2 (range 1.4–32.9) months after thymectomy, and 12.7 (range 3–37.3) months after symptom onset. Eleven of these 13 patients (84.6%) developed GMG within 2 years of symptom onset. Of the 58 included patients, 24 (42.3%) were men and 34 (57.7%) were women, with a median age at symptom onset of 54.7 years. The clinical characteristics of the 13 OMG patients who converted to GMG and the 45 pure OMG patients are displayed in Table 14.5 montP = 0.022).Of the 52 patients who could be included in the CSR analysis, 16 (30.8%) achieved CSR at a median time of 28.7 (range 15–54) months after thymectomy. Fifteen (28.8%) patients showed improvement at the last follow-up. No significant difference was observed between the CSR-OMG and non-CSR OMG patients in terms of sex, OMG symptoms at onset, disease duration before surgery, surgical approach, tumour location, tumour size, or immunosuppressive treatment after surgery. However, patients who achieved CSR had a younger age of onset . RNS-positivity was associated with a trend for decreased probability of CSR (P = 0.063). Patients with thymic hyperplasia or stage I thymoma showed a significantly higher chance of achieving CSR (P = 0.010) compared with patients with stage II/III thymoma. Post-operative follow-up duration was markedly longer in the CSR group , indicating that, with the extension of follow-up time, more patients would achieve CSR and that 2 years may not be long enough to determine whether CSR can be reached. We believe that this follow-up duration difference also explained the surgical approach outcomes between these two groups, as unilateral video-assisted thoracoscopic surgery was routinely performed from 2012 to 2017 in our centre, while the sub-xiphoid method became mainstream in the recent 4 years (Table We then used receiver operating characteristic (ROC) curves to explore the best threshold for age   and histological subtype of B2/B3 thymoma (P = 0.008) were associated with increased risk of OMG conversion as compared with patients with RNS-negativity and histotype hyperplasia + AB/B1 thymoma , was calculated by using the Kaplan–Meier method. Among these variables, RNS-positivity (P = 0.048) was associated with a higher chance of achieving CSR. Patients with hyperplasia and stage I thymoma showed an increased chance of achieving CSR as compared to those with stage II–III thymoma (P = 0.014)  and histotype B2/B3 thymomas  were significantly associated with OMG conversion. On the other hand, thymic hyperplasia and Masaoka–Koga Stage I thymoma  were independently associated with CSR in OMG patients after thymectomy (Table P = 0.032), and an age at onset > 60 years was a significant negative predictor for achieving CSR . In multivariate Cox analysis, only RNS positivity was a significant positive predictor for OMG conversion . Thymoma histotype B2/B3 showed a positive association with OMG conversion compared to AB/B1, and stage II/III thymoma showed a negative association with CSR compared to the stage I counterpart. However, neither reached statistical significance  subtype B2/B3 thymomas were significantly associated with post-thymectomy OMG conversion. On the other hand, thymic hyperplasia and Masaoka–Koga Stage I thymoma were independently associated with post-thymectomy OMG CSR.Thymectomy is required for patients with thymoma. Its role in non-thymomatous OMG (NTOMG), however, remains highly controversial . In our Although no correlation was detected between OMG generalization and AChR Ab status, our study showed that patients who were seronegative for AChR Abs were more likely to achieve CSR after thymectomy. Using standard assays, AChR Abs are detectable in approximately 50% of patients with OMG and in nearly 90% of patients with GMG . Anti-muThe presence of comorbidities at disease onset has been described as a risk factor for conversion to GMG . We did At our institution, we consider a minimum of 3 months of isolated ocular disease as an inclusion criterion. This 3-month duration is in keeping with the views of other studies . Monsul Our analyses did not identify age as a risk factor for OMG conversion. The effect of age on OMG conversion to GMG is paradoxical among studies. Feng et al.  revealedP = 0.002), log-rank test (P = 0.002), and multi-variable COX regression analysis (P = 0.022). Moreover, RNS-negativity tended to be associated with a greater likelihood of CSR, although the difference did not reach statistical significance. The association between RNS and OMG conversion was reported by other studies [Our study showed that RNS-positivity was strongly associated with OMG conversion in univariable analysis ( studies . Kim. et studies  revealed studies . Since lPrevious studies have reported the effect of prednisone in delaying onset of GMG as well as its sustained benefit in reducing the incidence of GMG and controlling diplopia , 23. GenLimited studies have discussed the importance of tumour size and location in determining clinicopathological features or its relationship to thymoma or MG prognosis. Tian et al. reported that thymomas located in the superior mediastinum were more likely to be associated with disease progression and tumour recurrence than those located in the inferior mediastinum . OkumuraFew studies have specifically studied OMG remission after thymectomy. Liu et al.  reviewedThe limitations of this study should be acknowledged. First, the current study had a retrospective design, which may have caused selection bias. Second, the number of patients with post-thymectomy OMG was small. The risk factors identified from this limited sample size may not be generalizable for all patients. Third, given the difference in follow-up duration between groups in our CSR analysis, our inclusion criterion of a follow-up period of 2 years may have caused selection bias, which might have influenced the CSR rate and other associated risk factors. Fourth, only AChR-Ab and MuSK-Ab status was tested in our study. Whether other autoantibodies, such as anti-LRP4 Abs and anti-cortactin Abs would present as confounding factors remains unknown. Finally, considering the different aetiology and pathogenesis of thymoma and thymus hyperplasia, the rationale of combining patients with hyperplasia and specific subtypes of thymoma is debatable.In conclusion, we revealed the impact of thymus pathology and thymoma anatomical features on prognosis of OMG after thymectomy. We found that RNS-positivity and histotype B2/B3 thymoma were independent predictors of OMG conversion to GMG. On the other hand, thymic hyperplasia and stage I thymoma independently predicted CSR after thymectomy. Patients with a younger age of onset and who are negative for anti-AchR Abs may also have a higher chance of achieving CSR. Further prospective studies with a larger number of patients are warranted to validate our findings.


Two studies showed improved overall survival after SRT plus immunotherapy in melanoma cancer patients with brain metastases. Three studies reported data on LC and DFS showing as SRT plus immunotherapy did not improve local control and DFS rates. G3-G4 toxicity was reported in only one study (20% in the SRT plus immunotherapy group versus 23% in the immunotherapy group). Despite SRT plus concurrent immunotherapy seems associated with possible survival advantage and low ≥ G3 late toxicity rates, the quality of evidence is very low. Therefore, in patients with brain metastases from melanoma, SRT plus immunotherapy should be evaluated on an individual basis after discussion by a multidisciplinary team.Aim of this study was to systematically review the literature to assess efficacy and safety of stereotactic radiotherapy (SRT) in combination with immunotherapy for the treatment of melanoma brain metastases (MBM). The literature was searched using PubMed, Scopus, and Embase. Studies comparing SRT The online version contains supplementary material available at 10.1007/s11547-022-01503-7. Immune checkpoint inhibitors and targeted therapies have demonstrated to enable long-term disease control in a high percentage of patients with metastatic melanoma; however, prognosis of patients with melanoma brain metastases (MBM) remain poor, with 17–22 weeks median overall survival from the time of diagnosis .plus nivolumab combination. [Data on the efficacy of immunotherapy in patients with MBM are limited having generally been excluded from clinical trials. In phase II studies, where patients with metastatic melanoma and at least one brain metastasis were included, both anti-CTLA-4 (ipilimumab) and anti-PD1 (nivolumab and pembrolizumab) antibodies achieved response rates of 10–24% for ipilimumab , 6, and ination. plus concurrent immunotherapy could be a combined modality treatment theoretically associated with improved patient outcome. However, synergy between RT and immunotherapy should be clinically and radiologically supervised, due to potentially increased risk of either RT-induced or immune-mediated toxicity. In particular, RT-induced toxicity could be increased by endothelial apoptosis and neuroinflammation produced by immunotherapy. The risk of brain toxicity is associated with tumour size, exposure to higher doses of RT, and concurrent use of chemotherapy. The safety of this combined approach has been extensively analysed in a recent review including data from a large number of retrospective studies [At the same time, SRT became largely available and nowadays it was increasingly used in MBM. In fact, stereotactic radiotherapy (SRT) in patients with MBM plays a key role due to excellent local control rates, minimal invasiveness, and possibility to repeat the treatment in case of new lesions. The effects of radiotherapy (RT) on both tumour cells and non-malignant tissues implicate a complex interaction with the immune system, resulting in both immunostimulatory and immunosuppressive outcomes. Advantages of RT are the enhancement of the immune-checkpoint inhibitors antitumour effects through increased production of cytokines and endogenous danger signals, tumour microenvironment changes, promotion of tumour-associated antigens presentation on antigen- presenting cells, and stimulus to T cell repertoire diversification . Based o studies . The rev studies .The present systematic review was performed to assess the efficacy and the safety of SRT in combination with immunotherapy for the treatment of MBM compared to SRT alone or immunotherapy alone in terms of overall survival, local control, disease free survival, melanoma specific survival, and late ≥ G3 toxicity.plus immunotherapy (I) superior when compared to SRT alone or immunotherapy alone (C), in relation to the outcomes (O) of benefit and harm? Supplementary 1 reports the development of GRADE  Recommendation.The clinical question was developed based on the P.I.C.O. framework as: population (P), intervention (I), comparison (C), and outcomes (O). The clinical question was: (P) in melanoma brain metastases, is SRT plus immunotherapy in brain metastases from melanoma  of the publication was considered. Studies were identified through a search process performed by three independent reviewers , and uncertainty regarding eligibility was resolved by a multidisciplinary committee . Eligible citations were retrieved for full-text review. An external expert committee defined the outcomes of benefit and harm . A multidisciplinary master board  coordinated the project and performed the final independent check and the definitive approval of the review. The GRADEpro Guideline Development Tool (GDT)  was used to create Summary of Findings tables in Cochrane systematic reviews (Supplementary 3). The quality assessment showed high clinical and methodological heterogeneity and risks of bias in the included studies, making quantitative synthesis inappropriate. Therefore, meta-analysis outcomes were not reported.The systematic review was conducted in accordance with the PRISMA guidelines . We perfoma Fig. . ClinicaThe external expert committee identified the following outcomes of benefit: overall survival , melanoma specific survival , disease free survival  and local control . The identified outcome of harm included acute and late ≥ G3 toxicity. All these outcomes were considered as “critical” for the decision-making process.Certainty of evidence for all selected outcomes was performed according to the GRADE approach, considering study limitations, imprecision, indirectness, inconsistency, and publication biases. Certainty level starts at higher pre-specified level for randomized controlled trials, but levels of certainty can be downgraded if limitations in one of the above-mentioned domains are detected. Evidence was classified as having high, moderate, low, and very low level of certainty.Based on the summary of evidence, the following judgments about the benefit-to-risk ratio between intervention and comparison were stated: favourable, uncertain/favourable, uncertain, uncertain/unfavourable, and unfavourable (both for intervention or comparison). The strength of the recommendation is considered as strong positive, conditional positive, uncertain, conditional negative, or strong negative.Seventy potentially relevant studies were identified through the database searches after duplicates and title removal. After screening of title and abstract, 53 papers were excluded. Of the remaining 17 papers, 13 were excluded through the full text examination for the following reasons: (1) the majority of patients received whole brain RT prior to SRT and those who received SRT were not separated in a way allowing for data extraction; (2) a small minority of patients received SRT but data on their primary or secondary outcomes measures was not reported and therefore could not be extracted for the analysis; (3) few patients (< 10) were enrolled; (4) a comparison group was lacking  and for SRT or immunotherapy alone was 54.5 years (range: 27–91 years). The most commonly used immunotherapy drugs were pembrolizumab and nivolumab, which were used in two out of four studies [plus immunotherapy group and in the SRT or immunotherapy group, 90 and 145 patients underwent prior systemic therapy, respectively.The median age for patients treated with SRT  studies , 13. Ipi studies . The mos studies  and Cybe studies , while i studies . Ninety- studies . One hunplus immunotherapy to SRT alone in patients with MBM. Twenty-six patients were treated either with SRT alone  or in combination with anti-PD-1 . Simultaneous treatment was defined as the somministration of the first dose of PD-1 inhibitor at least one week before SRT treatment and for at least six weeks after irradiation (n = 13). Non-simultaneous treatment (n = 13) was defined as the delivery of SRT at least three months after the last cycle of immunotherapy and at least six months before the first cycle. Patients with simultaneous treatment received at least three cycles of anti-PD-1 therapy with either pembrolizumab at a dose of 2 mg/kg every three weeks (n = 10) or nivolumab at a dose of 3 mg/kg every two weeks (n = 3). Eight (62%) of the combined treated patients were positive for BRAF mutation, five (38%) for NRAS mutation, and one for c-KIT mutation. In the SRT group, 10 (77%) patients were positive for BRAF mutation, one for NRAS mutation, and one for c-KIT mutation. A median of two (range: 1–5) lesions per patient were treated in the SRT plus anti-PD-1 group and a median of one (range: 1–3) in the SRT group. The median lesion size for the SRT plus anti-PD-1 group was 0.6 cm3 (range: 0.1–7.4 cm3) and 0.1 cm3 (range: 0.01–2.7 cm3) in the SRT group.The retrospective study of Trommer-Nestler et al . compareplus immunotherapy versus immunotherapy alone in patients with MBM. Simultaneous treatment was defined as the delivery of radiotherapy treatment 30 days before the first systemic therapy dose to 30 days after the first dose of the same therapy line. Non-simultaneous treatment was defined as the delivery of SRT ≥ 30 days before the start of the same therapy line. No significant differences in gender, LDH, BRAF status, age, performance Karnofsky status (KPS), tumour volume, number of lesions, and incidence of extracranial disease were found between the two groups. Fifty-eight (62%) of the simultaneously treated patients and ninety-six (57%) of the immunotherapy group were positive for BRAF mutation. Thirty-nine (42%) patients in the combined group and sixty-four (38%) in the immunotherapy group had more than three lesions.A prospective non-randomized study  comparedplus ipilimumab to SRT alone in patients with MBM, and found no significant differences in age, KPS, number of lesions, tumour volume, and incidence of extracranial disease between the two groups. A median of three (range: 1–9) lesions per patient was treated in the SRT plus ipilimumab group and in the SRT group. The median lesion size in the SRT plus ipilimumab group and in the SRT group was 0.6 cm3 (0.1–4.6 cm3) and 1.7 cm3 (0.2–8 cm3), respectively.In line with this study, Mathew et al.  comparedversus SRT alone in patients with brain metastases of melanoma. There were no significant differences between the SRT plus ipilimumab group and the comparison group. Seventeen (51.5%) of the simultaneously treated patients and three (25%) of the SRT group were positive for BRAF mutation. Fifteen (45.4%) patients in the combined group and twenty-one (56.7%) in the SRT group had 1–3 lesions.Finally, Silk et al.  retrospeAll four studies reported data on toxicity Table . G3-G4 tThe certainty of evidence was considered as “very low” for each outcome of harm for the following reasons: indirectness for population including both target therapy and immunotherapy13, imprecision for sample size12-15, and finally to possible selection bias due to a sub-group analysis. [plus immunotherapy in melanoma cancer patients with brain metastases [plus immunotherapy did not improve local control [Three studies reported OS rates , 15 and tastases , 15. Thr control –14 and D control , 14. Fin control , impreci control –15, and  control Table 3Suplus immunotherapy) did not increase the incidence of side effects (treatment-associated brain toxicity) compared to the control one . Moreover, SRT plus immunotherapy has proven effective in improving OS without benefit in terms of LC and DFS.In the MBM setting, the proposed intervention  immunotherapy and SRT have an almost additive effect considering the improved OS recorded in the combined modality treatment group, and (2) local response is greater and faster after SRT plus concurrent immunotherapy compared to SRT or immunotherapy alone. Heterogeneity in treatment protocols  and in the definition of "simultaneous" SRT plus immunotherapy combination, small patients population included in the selected studies, and selection biases could have affected the possibility to accurately define the effective role of SRT plus immunotherapy in this setting [In our systematic review, we examined whether SRT  setting –15. Therplus immunotherapy in MBM patients improves OS [Despite this limitations, two studies showed that the combination of SRT roves OS –15 withoroves OS –14 and Droves OS , 14. Morroves OS –19. Kiesroves OS . Similarroves OS .However, even if confirmed by the latter studies, the results of our analysis present paradoxical aspects. Indeed, an improvement in OS without prolonged LC and DFS is hard to be explained. Since this review is based on retrospective studies, selection bias could be hypothesized and in particular a preferential referral of patients with better performance status or with less relevant comorbidities to the combined modality treatment .vs 14.6 months; p < 0.001) [Nevertheless, these results are similar to the ones recorded in other oncological settings, showing an increased effect of immunotherapy given after RT. For example, the PACIFIC trial evaluated activity and safety of durvalumab administered after combined chemoradiation in patients affected by stage III NSCLC. In that trial, median time to death or distant metastasis was longer with durvalumab compared to placebo (23.2 months < 0.001) . Radioth< 0.001) , resulti< 0.001)  and it c< 0.001) .plus immunotherapy combination was confirmed, it would be useful to define which type of immune checkpoint inhibitor is more effective when combined to SRT. Lehrer et al. [plus SRT. However, these results may have been influenced by a higher number of lesions in the anti-PD-1 plus SRT group [In any case, if the positive effect of the SRT r et al. . suggestRT group .plus immunotherapy combination was found to have tolerable toxicity profile. In the SRT plus immunotherapy group (136 patients) intracranial haemorrhage was recorded only in eight patients [In the present systematic review, SRT patients , 15, heapatients . In the patients , 15, radpatients . In patiplus immunotherapy compared to single treatment groups.Limitations of our systematic review include the small number of studies, especially for the secondary outcome measures. In addition, none of them was a randomized controlled trial and all studies were retrospective. Toxicity data were extrapolated from retrospective studies with different adverse effects categorization and in some cases with short follow-up. More generally, a median follow-up of 6.9 months (range: 0.2–58.4 months) is insufficient to allow a proper assessment of late toxicity. However, longer follow-up is unlikely to lead to the detection of further differences in late adverse events between patients treated with SRT plus immunotherapy should be evaluated on individual basis after discussion by a multidisciplinary team”. The communication with the patient should include the following topics: prognosis with and without treatment, limited power of evidence on the benefit derived from treatment combination, and treatment related risks including haemorrhage and radiation necrosis.The final recommendation released by the panel was: “In patients with brain metastases from melanoma, SRT Supplementary file1 (DOCX 13 kb)Supplementary file2 (DOCX 19 kb)Supplementary file3 (DOCX 19 kb)Supplementary file4 (DOCX 13 kb)Below is the link to the electronic supplementary material.


FGL1 gene associated with pig productive traits to enrich the genetic marker pool for further selection and to support the studies on FGL1 in the context of the fat deposition (FD) process. The variant calling and χ2 analyses of liver RNA-seq data were used to indicate genetic markers. FGL1 mutations were genotyped in the Złotnicka White (n = 72), Polish Large White (n = 208), Duroc (n = 72), Polish Landrace (PL) (n = 292), and Puławska (n = 178) pig breeds. An association study was performed using a general linear model (GLM) implemented in SAS® software. More than 50 crucial mutations were identified in the FGL1 gene. The association study showed a significant effect of the FGL1 on intramuscular fat (IMF), loin eye area, backfat thickness at the lumbar, ham mass (p = 0.0374), meat percentage (p = 0.0205), and loin fat (p = 0.0003). Alternate homozygotes and heterozygotes were found in the PL and Duroc, confirming the selective potential for these populations. Our study supports the theory that liver FGL1 is involved in the FD process. Moreover, since fat is the major determinant of flavor development in meat, the FGL1 rs340465447_A allele can be used as a target in pig selection focused on elevated fat levels.The goal of this study was to evaluate the effects of mutations in the  Next-generation sequencing (NGS) technology is currently widely applied to predict processes associated with fat deposition and obesity-related events ,2. BesidFGL1) is a member of the fibrinogen family mainly synthesized in the liver [FGL1 expression is related to the regeneration of the liver organ by stimulating 3H-thymidine uptake leading to hepatocyte proliferation [FGL1 is also expressed in brown adipose tissue (BAT) and during liver injury; expression is also upregulated in this tissue, which suggests cross-talk between an injured liver and bAT. Consistently, a study of Fgl1-deficient mice showed global metabolic disorders, namely FGL1-null mice were heavier, had abnormal plasma lipid profiles, fasting hyperglycemia with enhanced gluconeogenesis, and exhibited differences in white and BAT morphology regarding wild types [FGL1 likely plays a crucial role in lipid metabolism and liver regeneration. On the other hand, FGL1 expression has been examined in gastric cancer (GC) tissue [FGL1 promotes GC proliferation, and patient overall survival time with increased FGL1 expression was significantly shorter. Therefore, the FGL1 gene has been proposed as a predictor in GC patients and a target for treating this cancer type. Wang et al. [FGL1 expression in the plasma of cancer patients is related to poor prognosis.Fibrinogen-like protein 1 (he liver . It has feration . FGL1 isld types . The aut) tissue , where Fg et al.  showed tPigs are a highly suited animal model for predicting FD events due to many convergences with the human body, such as the size of particular organs , body fa2 test pinpointed mutations characterized by significantly different allele distributions between the FD pig groups. Following this work scheme, we found FGL1 variants highly interesting regarding the possible application in the selection process.In the present study, Złotnicka White (ZW) pigs were used as an animal model in the context of FD processes. ZW is a Polish indigenous breed included in the Polish Animal Genetic Resource Conservation Program  and has Samples were collected after slathering in the Pig Test Station . Following carcass evaluation, the meat was intended for sale and consumption. Ethical review and approval were waived for this study due to a non-invasive method of collecting. All conducted research was approved by the Approving Experiment Committee of the National Research Institute of Animal Production  according to the Polish Act on the Protection of Animals Used for Scientific or Educational Purposes of 15 January 2015, which implements Directive 2010/63/EU of the European Parliament and the Council of 22 September 2010 on the protection of animals used for scientific purposes. Moreover, all procedures followed the guidelines and regulations of the Local Krakow Ethics Committee for Experiments with Animals.ad libitum to the final weight of 100 ± 2.5 kg. During pig maintenance at the PTS, growth performance such as feed intake, feed conversion, and daily gain were measured. After slaughter and detailed dissection, body composition traits were measured, including meat percentage, carcass yield, weight of the most significant cuts such as ham and loin, backfat thickness, and numerous fat-related traits, including visceral and subcutaneous fat content and meat quality traits such as intramuscular fat (IMF), pH, meat color, and myowater exudation [Female pigs of Złotnicka White were used in RNA-seq n = 16) and association (n = 72) analyses. The animals with an initial weight of 30 kg were delivered to the Pig Test Station (PTS) of the National Research Institute of Animal Production from different farms. The animals were maintained under the same environmental and diet conditions according to a local procedure , feeding and assoLiver samples (n = 72) were collected within 20 min after dissection and stabilized in RNAlater™ Stabilization Solution , and then frozen at −20 °C. Next, two pig groups were selected based on fat-level measurements performed 24 h after slaughter. The RNA-seq experiment included 16 ZW pigs, with 8 representing high-fat deposition  and low  values.FGL1 variant frequency was estimated in Polish Large White (PLW) (n = 208), Polish Landrace (PL) (n = 292), Puławska (n = 178), and Duroc (n = 72) pigs that are still active in the Polish breeding. Animal samples for DNA isolation were collected as blood or hair follicles and were banked in the National Research Institute of Animal Production as part of other research projects.Moreover, As described previously by Piórkowska et al. , RNA was2 test  ≤ 0.05) between the HFD and LFD pigs were estimated. The FDR correction was conducted using the Rstats base procedure and default parameters. In the χ2 test, it was expected that allele/genotypes would have normal according to Gaussian distribution. The procedure in R was based on Benjamin and Hochberg [https://string-db.org/).Picard tools and GATK v. 4.1.9  were useHochberg . FunctioFGL1 variants located in the 3′UTR region, according to the χ2 test, were validated by Sanger sequencing of DNA. The primers for sequencing are shown in FGL1 gene were submitted to GenBank with access number MW827172 (NCBI database). miRBase v.22 and mirPath v3.0 (Diana) tools we used to analyze significant SNPs and indels identified in the 3′UTR regions for miRNA binding and miRNA functional analysis, respectively.Four of the most significant Linkage disequilibrium was estimated with analysis based on Barrett et al.  method.FGL1 3′UTR genotyping, PCR-RFLP, Sanger sequencing, and PCR-ACRS methods were designed. The primers and restriction enzymes are shown in FGL1 frequency was estimated for ZW (sows), PLW (boar and sows), PL (boars), Puławska (boars and sows), and Duroc (boars) pigs. Besides ZW, all individuals used in the study are still active in Polish breeding. The examination of FGL1 variants frequency allowed us to establish the selective potential targeted to increase organoleptic qualities of pork lost in the previous intense breeding.For The differences in fat deposition traits and pig phenotypes, including 16 ZW pigs used previously in RNA sequencing analysis, were calculated between HFD and LFD using the ANOVA procedure (SAS v. 8.02) with a post-hoc Duncan test (SAS Enterprise).RYR1 mutation was genotyped in the ZW population. All individuals included in the analysis were free of the RYR1 alternate allele [Association analysis was performed, including 72 ZW pigs using the GLM procedure (SAS v. 8.02). Additionally, severely affected pig phenotype e allele .ijk—observation, µ—overall mean, di—fixed effect of genotype group, bj—fixed effect of the breed, α(xijk)—covariate for weight of the right side of the carcass, and eijkl—random error. The GLM model for analysis within breeds omitted bj—fixed effect of breed. The ratio between investigated pigs and their mothers (sows) was 1.7, and the ratio between investigated pigs and their fathers (sires) was 2.28; therefore, these factors were not included in the statistical model. During the whole year, the animals were maintained in the pig house at the same temperature and humidity conditions and with the same feeding; therefore, the model did not account for the effect of slaughter season. The least-square means (LSM) method was used for the determination of significant differences between genotype groups. The differences in phenotype in particular genotype groups are presented as LSM ± SE.The general linear model (GLM)  was used for statistical analyses. The linear model for fixed analysis was:Additive and dominance effects were calculated for a total of 72 pigs. Additive and dominance effects were calculated using the regression (REG) procedure (SAS v. 8.02). The additive effect was denoted as −1 and 1 for genotypes AA and GG, respectively. The dominance effects are represented as −1 for AG heterozygotes and 1 for both homozygotes.HFD pigs used in the experiment showed over 40% higher fat deposition in the lumbar location and over 30% higher FD according to average backfat thickness and peritoneal and loin fat than in LFD individuals. Analysis of FGL1 expression between high and LFD pigs showed that in 180-day-old animals, FGL1 was not differentially expressed . Table 12 test was 356. There were close to 2500 3′UTR significant variants. Significant downstream and intron mutations were numerous, over 2000 and 3500, respectively. Downstream and intron mutations are probably related to non-coding but functionally transcribed active genomic regions or unannotated exons  showed that 70.8% of uniquely mapped reads matched the annotated exon regions, and 16.5% matched the introns. Over 100,000 mutations were identified in analyzed pigs, of which over 7000 showed significant differences in genotype distribution between HFD and LFD groups. It was found that 73.8% of identified mutations belonged to known variants deposited in the NCBI database. The number of insertions and deletions constituted a mere 7%, and significance according to the χed exons . HoweverFGL1 variants were chosen because the FGL1 plays an important role in the liver, the major organ for converting excess carbohydrates and proteins into fatty acids and triglycerides then exported and stored in adipose tissue [FGL1 is often mentioned in publications as co-expressed  mutations as significant revealing differences in genotype distribution between the analyzed FD pig groups. The lowest chicq value (0.000335463) for 10 mutations in the 3′UTR region was observed. Haplotype analysis and visualization of linkage disequilibrium, including all SNPs, showed that they were clustered in a few blocks . FGL1 mutation genotyping. New indel mutations were submitted as new alleles of the FGL1 gene to GenBank under accession number MW827172.Four of the identified 3′UTR p < 0.001) at three measured points of lumbar, 800 and 730 g (p < 0.001) heavier loin and ham fats, respectively. The differences between the FGL1 genotypes are shown in Preliminary association analysis, including 16 pigs that differed in fat deposition (the same as in the RNA-seq method), showed that 10 fully linked 3′UTR polymorphisms were significantly associated with fat deposition. Although only two alternative homozygous animals were found (AA-rs340465447 or CC-rs330493983), the heterozygous animals were quite distinct in FD traits from reference homozygotes. They showed almost 1 cm thicker backfat (n = 72), showed that polymorphism linkage was not as strong as in the 16 individuals selected for RNA sequencing. Two SNPs were fully linked but revealed a slightly different allele distribution than observed for two indel mutations  and NC_010459.5:g.5549161insCAGCA (C/CAGCA) FGL1 mutations of the 3′UTR region, including the more numerous Złotnicka White population (utations . For NC_p < 0.01) of ABT, +2.90 cm2 (p < 0.01) of loin eye area and +9 day (p < 0.05) of slaughter age. The rs340465447 mutation leads to changes in daily gain and pH of loin and ham values measured 24 h after slaughter  and NC_010459.5:g.5548991-5548992del (TCA/A) and showed that these SNP mutations are associated with IMF and subcutaneous fat deposition traits. Pigs with the AA genotype showed 24%, 23%, and 32% higher IMF, ABT, and loin fat, respectively. Additive effect analysis confirmed this observation and showed that a change A → G leads to −0.24 cm (laughter .p < 0.01) of meat percentage, +280 g (p < 0.05) of ham mass and −0.32 cm (p < 0.01) in backfat thickness in the K1 point—over the lateral edge of the longissimus dorsi muscle (The NC_010459.5:g.5548991-5548992del (TCA/A) polymorphism influenced fat and meat traits, such as loin and ham mass, meat percentage, loin eye area and primary cuts, and different kinds of subcutaneous fats, such as average backfat thickness and loin and ham fats. In turn, for IMF, only a value of trend was observed. The dominance effect comparing heterozygous with homozygous values showed that changes ins/del → ins/ins leads to +2.04%  or insertion NC_010459.5:g. 5549161insCAGCA(C/CAGCA) showed a lower frequency. Only heterozygotes were observed in the PL, and none of the alternate homozygote pigs were found .At the end of the 20th century and the beginning of the 21st century, the rate of life significantly accelerated due to vast civilization leap, the development of science, and access to new technologies. The consequence of increased stress levels resulted in civilization diseases, such as obesity leading to substantial health disorders such as diabetes , hyperteMC4R) gene, the mutation described by Kim et al. [MC4R.The molecular process associated with fat accumulation is often challenging in humans; the specific clinical and physiological conditions related to obesity may be limiting due to costs or complexity, the difficulties in obtaining appropriate tissue samples, or ethical problems. Thus, researchers use animal models where molecular DNA/RNA/protein functions remain unchanged between species. Pig animal model better reflects the processes occurring in humans than small lab animals, as they show human-like body proportions , metabolm et al. , was foum et al. . A few ym et al.  found seFGL1 gene, which were significantly related to fat deposition in Złotnicka White (ZW) pigs using variant calling methods based on RNA-seq data. We found more than 50 polymorphism sites that, according to the χ2 test, showed significantly different genotype/allele distribution when comparing low- and high-fat deposition pig groups. Most of them were located in the 3′UTR region, which controls gene expression and does not change the amino acid sequence. As previously mentioned, FGL1 is expressed mainly in the liver and is related to the regeneration of this organ, being involved in the hepatocyte proliferation process [FGL1 gene leads to increased body weight and an abnormal plasma lipid profile. Nevertheless, RNA-seq data used in the present study for gene variant identification showed that FGL1 was not differentially expressed between high- and low-FD pig groups at 180 days old. However, these findings do not preclude prior differentiation at the beginning of ontogenetic growth or in an embryonic stage.The present study identified mutations in the  process . Demchev process  suggesteFGL1 is often mentioned in the publications as co-expressed in the liver or plasma with apolipoprotein C3 (APOC3), apolipoprotein A1 (APOA1), and apolipoprotein A2 (APOA2), which are strongly associated with the regulation of very-low-density lipoproteins, cholesterol efflux, and transport, and triglyceride catabolic process with [Moreover, our String v. 11.0 analysis showed that ess with .FGL1 3′UTR variants change binding sites for numerous miRNAs previously described as playing a role in regulating lipid processes related to diabetes, appearing as potentially regulating porcine FGL1 gene expression, such as mir338-5p and mir338-3p. Their binding site was probably controlled by rs330493983 FGL1 SNP, which revealed a significant effect on fat deposition in pigs. The T variant of rs330493983 occurring in lean pigs favors miRNA-338 binding, whereas the C variant precluded interacting with this regulator. miR-338-3p is expressed in the liver and is related to cancer pathogenesis [FGL1, which Demchev et al. [FGL1-null mice. Thus, the binding site in the 3′UTR region significantly affecting FD in pigs indicates likely regulation of mir-338-3p-FGL1. However, it should be confirmed in further experimental research, including cell culture and luciferase assay.It is assumed that identified significant ogenesis ,42. Howeogenesis  showed tRYR1 gene and eliminating carriers and burdened individuals from the dam and sire populations. Moreover, the Polish Ministry of Agriculture and Rural Development presently funds the monitoring of IGF2 and MC4R polymorphisms [Long-term selection toward lean meat in pigs, both in the breeds used as dam and sire lines, has led to decreased backfat thickness and IMF, which determine meat flavor and technological suitability . The attorphisms ,44 in PLFGL1 3′UTR variants was tested in the ZW breed, which is not under selection pressure, so within this population, a wide range of fat-related and meat traits is represented; thus, ZW is a suitable material for association study. Our research showed for interesting correlation of rs340465447_A, rs330493983_C, NC_010459.5:g.5548991-5548992del_A and NC_010459.5:g.5549161insCAGCA_CAGCA FGL1 alleles that were positively associated with subcutaneous fat and also IMF. Identification of these alleles in Polish pig populations used as maternal and paternal components in breeding was carried out. Their presence in these populations was rather poor. However, in the PL and Duroc pigs, allele rs340465447_A occurred in the alternate homozygous form, which is promising if breeders would try to introduce this selection marker to increase fat levels, especially as only boars were analyzed in the PL and Duroc; therefore, its spread in the PL population would be easier.In the present study, the possibility of using FGL1 is indirectly related to the occurrence of obesity and diabetes. Our study supports this theory because we detected interesting FGL1 variants in the 3′UTR region using liver RNA-seq data related to fat levels in the pig carcasses. We indicated that identified mutations are probably associated with miRNA binding, which regulates FGL1 expression, and probably fat deposition in pigs. Moreover, association analysis in ZW pigs pinpointed the possibility of the FGL1 variant, especially rs340465447_A utility, in the selection process toward increasing fat level in pigs since fat is the leading meat flavor carrier.Mice and human studies show that


The therapeutic effect of drugs for functional dyspepsia (FD) is still limited. Ganoderic acid A (GAA) has anti-inflammatory and cellular protective activities. The aim of this study is to explore the therapeutic effect of GAA on FD.  The FD rat model was established via tail damping and forced exercise fatigue. The gastric emptying rate and intestinal propulsion rate of the rats in each group were then detected, and the pathological damage of gastric antrum and duodenum tissues was observed by hematoxylin-eosin (HE) staining. An enzyme-linked immunosorbent assay (ELISA) was conducted to determine the levels of motilin (MTL), vasoactive intestinal peptide (VIP), leptin, gastrin (GAS), calcitonin gene-related peptide (CGRP), and somatostatin (SS) in plasma, and Western blot was used to detect the protein expression levels of occludin, zonula occluden-1 (ZO-1), and junctional adhesion molecule-1 (JAM-1) in the duodenal tissue.  Treatment with GAA significantly raised the gastric emptying rate and intestinal propulsion rate of FD rats and histologically alleviated the gastric and duodenal damage. Meanwhile, GAA positively regulated the secretion of brain-gut proteins, such as upregulation of MTL, GAS, and SS and downregulation of VIP, leptin, and CGRP. In addition, GAA treatment increased the protein expression levels of occludin, ZO-1, and JAM-1 in the duodenal tissue of the FD rats.  GAA may exhibit protective effects on FD by regulating the secretion of brain-gut peptide, protecting the intestinal barrier and improving gastrointestinal motility. Functional dyspepsia (FD), also known as nonulcer dyspepsia, is one of the most common functional gastrointestinal disorders. FD is usually characterized by epigastric pain, persistent and recurring epigastric bloating, early satiety, anorexia, nausea, and abdominal discomfort, etc. . It is rGanoderma lucidum (G. lucidum) is a large white-rot fungus which belongs to basidiomycete. It has an applicative history of 2000 years in China and other Asian countries and has been regarded as a beneficial food to the body all the time [G. lucidum has the potential to treat diseases. The root bark, mycelium, and spores of G. lucidum contain about 400 different biological active compounds, mainly including triterpenoids, polysaccharides, nucleotides, sterols, steroids, fatty acids, proteins/peptides, trace elements, and other substances [G. lucidum pills can promote the healing of chronic gastric ulcers induced by ethanol and significantly improve gastric mucosal injury [β, IL-6, and TNF-α release from mouse-derived cortical microglial cells when inhibiting the expression of nuclear factor (NF)-κB (p65) [the time . With thbstances . These cbstances . And stul injury . Triterpl injury . Ganoderl injury . StudiesκB (p65) . HoweverThis study was approved by the Ethics Committee of Xiangyang Central Hospital (C202205-8), and the relevant experiments were carried out in accordance with the approved guidelines. Domperidone maleate  was purchased from Janssen Pharmaceutical Co., Ltd. . GAA was obtained from Med ChemExpress . Following the method of Liang et al. , the FD A total of 24 adult male SD rats weighing 180–220 g were selected and randomly divided into four groups: the control group, the FD model group, the GAA-treated FD model group, and the DOM-treated FD model group. Rats in the control group received a normal diet and an equal volume of normal saline (NS) via intragastric administration every day. The other rats were induced FD and 10 days later, they received an equal volume of NS, 40 mg/kg GAA, or 3 mg/kg domperidone (Dom) through stomach perfusion every day for four weeks, respectively. After the last gavage, the rats in each group were fasted for 24 h. On the next day, three rats in each group were randomly selected for abdominal aorta blood sampling under anesthesia.W1. After removing the gastric contents, the stomach was dried with a filter paper and the dry weight (W2) was measured with the weight of the nutritional semisolid paste recorded (W3). The gastric emptying of rats in each group was calculated using the following formula: gastric emptying = (W1 − W2)/W3 × 100%, and the intestinal propulsion rate was calculated as well by using the following formula: intestinal propulsion rate = L2 (the distance semisolid paste travels from the pylorus)/L1  × 100%.Rats in each group were fed with nutritional semisolid paste (2 mL) by gavage and euthanized after 30 min. The abdominal cavity was then opened to ligate the cardia and pylorus of the stomach, followed by excision of the entire stomach and small intestine. The whole stomach was weighed to get The rat gastric and duodenal tissues were fixed in a fixative, embedded in paraffin, and cut into sections. The sections were stained according to the instructions of the HE staining solution and observed and photographed under a microscope.The blood sample was allowed to stand for 30 min and then centrifuged at 4°C at 2000 r/min for 20 min. The supernatant was collected into new centrifuge tubes and stored in a −80°C refrigerator. The serum levels of motilin (MTL), vasoactive intestinal peptide (VIP), leptin, gastrin (GAS), calcitonin gene-related peptide (CGRP), and somatostatin (SS) were detected in accordance with the instructions of the corresponding ELISA detection kit . The absorbance value at 450 nm was also detected.μg of protein of the lysate was separated through sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), transferred on a polyvinylidene fluoride (PVDF) membrane, blocked in 5% nonfat dry milk for 1-2 h, and incubated with the primary antibodies , JAM-1, β-actin; all from Abcam ) overnight at 4°C and secondary antibodies (Abcam) at room temperature for 1 h. The membrane was rinsed before and after the secondary antibody incubation. Subsequently, the sample was developed with electrochemiluminescence (ECL)  and then photographed under a gel imaging system. With β-actin as the internal reference, Image J software was used to analyze the gray level of protein bands.The rat duodenal tissues were lysed with radio-immunoprecipitation assay (RIPA) lysis solution  and centrifuged at 12000 rpm/min at 4°C for 30 min to obtain the supernatant lysate. 20 t-test analysis were used for analyzing the difference between groups. p < 0.05 indicates significant differences.All results were analyzed by SPSS 26.0  software and expressed as mean ± standard deviation (SD). One-way ANOVA analysis of variance and independent sample p < 0.01), suggesting that the FD rat model was successfully established in this study. Then, FD rats were intragastrically administered with 40 mg/kg GAA and 3 mg/kg Dom (positive drug), respectively. As a sequence, the gastric emptying rate and intestinal propulsion rate of the GAA group and Dom group were significantly higher than those of the FD group (p < 0.01) with GAA exhibiting a greater therapeutic effect , indicating impaired intestinal barrier function. Importantly, these protein levels were significantly restored evidently in the presence of GAA (p < 0.05) . As revealed by Western blot, the protein expression levels of occludin, ZO-1, and JAM-1 in the duodenal tissue of the FD rats declined significantly ( Figures , suggestFD is a disease affecting many facets of patients' life , mainly M cells located in the proximal duodenum and acts as a stimulus to gastric antrum contraction, thereby exerting the function of signaling starvation [G cells in the stomach. These brain-gut peptides are all biomarkers reflecting the function of the gastrointestinal tract. Consistent with the results shown in the study of Liang et al. [Communication between the central and enteric nervous systems is indispensable to the links sustaining life activities. And peptides such as brain-gut peptides, distributed in both the gastrointestinal and nervous systems, act as messengers during this process. It is reported that FD patients with delayed gastric emptying had lower levels of SS, MTL, and GAS with elevation of VIP, leptin, and CGRP levels . Among tarvation . SS is rarvation . GAS is g et al. , we alsog et al. . When dyg et al. . It is ng et al. , 32. As g et al. . We founγ/CD36 signaling pathway [At present, quite a few studies have explored the mechanism underlying GAA in various diseases. For example, Wang et al. found that GAA contributes to inflammation and lipid deposition through the Notch1/PPAR pathway . Bao et  pathway . Zhang eCollectively, GAA may improve gastric emptying and intestinal propulsion through regulation of the secretion of brain-gut peptides to protect the intestinal barrier, thereby improving FD. This evidence highlights the potential of GAA to be a promising therapeutic drug for FD.


Lifestyle interventions are the first-line treatment for Type 2 diabetes mellitus (T2DM), highly prevalent in the community. This study aimed to examine the 8-week separate and combined effects of aerobic training (AT) and pomegranate juice intake (PJI) on insulin resistance and serum levels of liver enzymes, liver enzymes, and insulin resistance in men with T2DM.n = 10); AT (n = 10); PJI (n = 10), and control (C) (n = 10). The AT program consisted of 60–75% of maximum heart rate (HRmax), 40–60 min/day, and 3 days/wk. Participants in the PJI group consumed 240 ml of pomegranate juice (sugar or additive-free) daily for 8 weeks.This study evaluated the alterations of anthropometric indices, insulin resistance, and liver enzymes in 40 middle-aged men (40–50) with T2DM. Participants were randomly assigned into four groups: AT+PJI (AT+PJI, PJI, and AT groups decreased anthropometric indices, HOMA-IR, and liver enzymes after 8 weeks. In contrast, the C group significantly increased the mentioned variables after the intervention. The result showed that AT+PJI significantly lowered liver enzymes, anthropometric indices, and HOMA-IR than AT or PJI alone. Also, the results of this study showed no significant difference between AT and PJI groups. However, in these groups, significant improvements in these variables were observed compared to the control group.Due to the effect of combined AT+PJI in improving T2DM risk factors, it could be recommended for T2DM patients to prevent increased liver enzymes and insulin resistance.  Type 2 Diabetes Mellitus (T2DM) is the most common health problem , with moIt is known that diet and medication alone are not sufficient in treating and controlling blood glucose and lipid metabolism in human models of diabetes, and physical activity should be added to the daily schedule of these individuals . It has Some studies have investigated the different effects of AT and pomegranate juice intake (PJI) on T2DM –21. Howehttp://www.irct.ir: IRCT20200907048650N1. This research was conducted according to the Declaration of Helsinki. The Research Ethics Committees approved the study protocol of Kermanshah Razi University (IR.RAZI.REC.1398.007); informed consent was taken from all patients.This study was a single-blinded, placebo-controlled, randomized clinical trial among 40 T2DM patients aged 40–50 years that was registered on the website of the Iranian clinical trial at n = 10), AT (n = 10), PJI (n = 10), and control (C) group (n = 10). One participant in the AT group and one subject in the PJI group refused to continue the intervention program. . Due to the probability of refusal to continue the study, forty men (10 in each group) with T2DM, aged 40–50 years, were randomly selected. The voluntary sampling method was used among patients from the Diabetes Medical & Health Center, Kermanshah, Iran. Then subjects were randomly (using a random-numbers table) divided into four groups; AT+PJI  and used the 6–20 rating of perceived exertion (RPE) scale (Table max = 220− age]. The AT program was based on previous studies and the American Diabetes Association (ADA) [The 8-week exercise training program consisted of 40–60 minutes of jogging and running at 60–75% of maximum heart rate (HRmax) Table . All of model: FT and usedon (ADA) .Table 1AParticipants in AT+PJI and PJI consumed 240 ml of pure pomegranate juice from Orum Narin Company’s SHADLEE brand (without sugar and other additives) daily after lunch for 8 weeks. The Orum Narin Company confirmed that all juice bottles contain the same amount of energy and nutrients. A detailed description of the preparation of the pomegranate juice is reported elsewhere [Before the intervention, participants were thoroughly acquainted with the aims of the study, were taught to fill out the requested questionnaires appropriately, and received the necessary oral and written explanation. First, demographic data, health status, current alcohol intake, and medication were recorded from all participants. Before attending the training program, the participants filled out a detailed semi-quantitative food frequency questionnaire tailored to the Iranian population. It included everyday food items, portion sizes, and meals to record and analyze 3-day food recalls before and after the intervention. The Food Processor nutritionist four software (FPN4) was used to determine the food intake and macronutrient consumption . The participants were asked to consume the same food and macronutrient composition 1 day before collecting blood samples in the pre and post-tests. The participants’ diet consisted of 55% carbohydrates, 30% fat, and 15% protein.Three days before the intervention, height was measured to the nearest 0.5 cm using a stadiometer . Bodyweight (BW), Body mass index (BMI), waist-hip ratio (WHR), and body fat percentage (BFP) were obtained by a bioelectric impedance body composition analyzer  in the fasting state.Participants were asked to refrain from strenuous exercise 1 week before the blood sampling. In the laboratory, a blood sample of 10 ccs was taken from a brachial vein, centrifuged at 3000 rpm for 10 minutes, followed by serum isolation. The serums from blood samples were frozen at − 28 °C for testing. After a 12-hour fast, blood samples were taken in two phases, 48 hours before and after the first and last training sessions. Serum concentrations of liver enzymes  were measured using the Enzymatic Method with Autoanalyzer Kit . Fasting blood sugar was calculated using the enzymatic method using Pars Azmoon test kits (Iran), insulin by ELISA method using the Mercoda Company kit (Sweden), and Insulin resistance index was measured using the following formula .\documenThe results were analyzed using IBM SPSS (version 24.0). The descriptive statistics quantity was presented as the mean and the standard error of the mean (SE). The Shapiro–Wilk’s test evaluated the normality of distribution. One-way ANOVA and t-test were used to compare the mean hepatic risk factors between and within groups. Tukey’s post hoc test was used if significant differences were found.P = 0.001, P = 0.001, P = 0.001, and P = 0.001), AT , and PJI , while in the C, these variables increased significantly  , AT , and PJI  , insulin , and HOMA-IR  in the AT+PJI group compared to the AT and PJI groups alone; respectively. Furthermore, the results revealed significant differences between AT and PJI groups in FBS (P = 0.001), insulin (P = 0.024), and HOMA-IR (p = 0.022).There were significant differences in FBS, insulin, and HOMA-IR in post-test compared to pre-test in AT+PJI , AT , and PJI , as detailed in Table P = 0.029, and P = 0.001, respectively) in AT+PJI compared to AT and significantly lower GGT (P = 0.001) in AT+PJI compared to PJI.There were significant differences in the AST, ALT, and GGT between the pre-test and post-test in AT+PJI  , 34. TheThis study showed that 8 weeks of combined AT+PJI significantly decreased the liver enzymes  in the AT+PJI, AT, and PJI compared to the control group. This decrease was significantly higher in AT+PJI than in AT or PJI alone. Pomegranate juice might decrease the activity of ALT, AST, and GGT enzymes probably by reducing blood glucose, glycation of antioxidant enzymes, and increasing the clearance of ROS . As pomeSmall sample size, not evaluating HbA1c index, single blind design, and not checking the nutritional profile of the pomegranate juice were among the limitations of the present study.Finally, both separate or combined AT and PJI improve anthropometric indices, insulin resistance, and liver enzymes in men with T2DM. However, combined AT+PJI induces more favorable improvements. Due to the effect of combined AT+PJI in improving T2DM risk factors, it could be recommended to T2DM patients to prevent increased liver enzymes and insulin resistance in these.


There is strong evidence demonstrating the incidence of Acute Coronary Syndrome (ACS) among patients with cirrhosis, with the initiation of antiplatelet therapy being subject to debate due to an increased risk of bleeding. This study aimed to determine mortality among patients presenting with concomitant Acute Variceal Bleeding (AVB) and ACS at Index admission. Furthermore, the recurrence of AVB and ACS among patients discharged with or without antiplatelet therapy was determined.This retrospective study was conducted at the Aga Khan University Hospital, Karachi, Pakistan on patients ≥ 18 years of age admitted to our ER with concomitant ACS and AVB between January 2002 to December 2017. Follow-up for 6 months or till death (if < 6 months), was observed, to help determine the incidence of recurrent AVB and ACS. The incidence of AVB and ACS was then compared amongst patient groups based on the usage of anti-platelet drugs on discharge.P = 1.000) and ACS (P = 0.091), depending on the use of antiplatelet therapy.A total of 29 patients were included, with a mean age of 58.7 ± 11.0 years. Seven patients died on admission, having worse underlying liver disease. No mortality was reported among the remaining 22 patients. All 22 patients underwent surveillance endoscopy with variceal band ligation until obliteration, as needed. Only 7 patients from the surviving cohort received antiplatelet therapy. After 6.05 ± 1.1 months of follow-up, 1/22 (4.5%) developed recurrent AVB and 2/22 (9.1%) developed cardiovascular events. Importantly, there was no significant difference in the incidence of recurrent AVB (Concomitant AVB and ACS is a severe disorder with increased mortality among cirrhotic patients at presentation. The incidence of AVB does not seem to exacerbate with the use of antiplatelet agents, provided successful obliteration of varices is achieved using elective band ligation. P = 0.001) , was present, defined as per the guidelines published in the European Heart Journal: AMI defined as an increase in high-sensitivity Cardiac Troponin T or I, with at least one value above the 99th percentile of the upper reference limit  and at least one of the following: symptoms of myocardial ischemia, new ischemic ECG changes, development of pathological Q waves on ECG, etc.; NSTEMI patients may also exhibit ECG changes such as transient ST-segment elevation, persistent or transient ST-segment depression, T-wave inversion, flat T waves, pseudo-normalization of T waves, or ECG may be normal . PatientRecords were reviewed until 6 months follow up, or till death (if < 6 months) from index admission, to determine the incidence of mortality at index admission, along with the incidence of recurrent AVB and ACS during follow-up. The incidence of recurrent AVB and/or ACS was then compared amongst patient groups based on the usage of anti-platelet drugs on discharge.Categorical variables were presented as frequencies and percentages, and continuous variables as means with standard deviations, or medians with their respective ranges. Chi-squared test and Independent student t-test were used for further statistical analyses, which were performed using SPSS V25.0.P-value of < 0.05 was considered statistically significant throughout our study.A Twenty-nine patients were found to have presented with concomitant AVB and ACS over the study duration, predominantly male [19/29 (65.5%)] with a mean age of 58.7 ± 11.0 years. Twenty-five patients (86.0%), presented predominantly with UGB symptoms such as hematemesis and melena. Decompensated Cirrhosis was present in 19/29 (65.5%) patients and a total of 14/29 (48.3%) patients presented with Ascites, in which there was an equal distribution of 50% between mild-moderate and severe ascites. A majority of patients presented with NSTEMI [24/29 (82.8%)], followed by STEMI [5/29 17.2%)]. Other baseline characteristics are presented in Tables .2%]. Othn = 2) and renal (n = 3) failure, and a brain infarct (n = 1). There was no mortality in the remaining 22 patients, within their 6 months of follow-up.A total of 7/29 (24.1%) patients died at Index admission. Two of the seven (28.6%) patients died secondary to cardiac causes: one due to heart failure, and the other because of bradycardia with underlying heart block. Two patients (28.6%) had fatal re-bleeding, one of whom was managed with Trans-jugular Intrahepatic Porto-systemic Shunt (TIPS), while the other patient was too critical to undergo any intervention. The remaining 3 patients (42.8%) died secondary to sepsis with multi-organ failure, comprising of respiratory (n = 22) and the patients with mortality (n = 7) revealed the underlying liver disease was worse in patients who died compared to the survivors, as shown with significantly higher CHILD-PUGH  and MELD  scores, as well as lower albumin (g/dl) at presentation . Ascites was not found to play a significant role in determining mortality . Additionally, patients in the non-surviving cohort had a statistically significant higher drop in mean hemoglobin (g/dl) from baseline at Index admission than those patients who lived . There was no other significant association between the two groups.Baseline comparison between the surviving patient cohort  received antiplatelet therapy in the form of a single antiplatelet agent (SAPT)  75 mg or Clopidogrel 75 mg; Once Daily). The median time to start patients on their anti-platelet regime was 3.0 days (0–60.0), while the mean follow-up duration (months) was 6.05 ± 1.1 months. All 22 patients underwent surveillance endoscopy after 2 weeks of Index admission, and varices were band-ligated, with follow-up surveillance and further band-ligation until obliterated.. Importantly, the incidence of recurrent AVB (P = 1.000) and ACS (P = 0.091) did not depend on the use of antiplatelet therapy (Table ). This episode of AVB on follow-up was noticed in a patient who only had a single session of EVBL. Of note, a total of 9 patients had only 1 session of EVBL, while the remaining 13 underwent ≥ 2 sessions of EVBL, including Index admission plus subsequent surveillance band ligation .Only 1/22 (4.5%) patients developed re-bleeding from varices and 2/22 (9.1%) developed recurrent episodes of ACS py Table . This epWe aimed to assess the survival outcomes in cirrhotic patients presenting with concomitant ACS and AVB and the role of anti-platelet agents. Our study has demonstrated high short-term mortality (24.1%) amongst patients with concomitant AVB and ACS, with increased severity of underlying liver disease in fatal patients. Moreover, the use of anti-platelet regimes was not significantly associated with either follow-up variceal bleeding or cardiac events.P < 0.001), with higher incidences of complications such as variceal bleeding, hepatic encephalopathy, and ascites  [P < 0.01) and gastrointestinal bleeding , although variceal bleeding did not have any significant association with Index mortality  [Our mortality rate is in concordance with published literature, which provides evidence of increased risk, as well as higher mortality rates of ACS in patients with underlying cirrhosis –20. Wu V < 0.01) . Recentl = 0.14) .P = 0.045), has been described as a significant predictor of death in cirrhotic patients [P = 0.215) in our patients, it was the most common sign of decompensation (526.6%). Ascites is usually the landmark sign in progression into the decompensated phase of cirrhosis, and depicts a worsening prognosis of CLD, with mortality estimated to be 50% in 2 years [Albumin, significantly lower in our deceased patient population  and mortality (P = 0.01) [UGB was the predominant complaint in most of our patients (86.0%). It is most frequently caused by AVB amongst cirrhotic patients and has been strongly associated with mortality in the presence of ACS , 28–30.  = 0.01) ; however = 0.01) .P = 1.000), and neither with recurrent cardiac events (P = 0.091), at 6 months of follow-up. Interestingly, 2 patients from the group treated with SAPT developed a recurrence of ACS, as compared to no recurrence of cardiac events in patients not receiving antiplatelet therapy. We postulate this to be attributable to various confounding factors that may have been present in those individual patients such as male gender, age, severity, site, and extent of luminal narrowing, and varied compliance to medications. Furthermore, SAPT has been shown to demonstrate a significantly higher incidence of ischemic events, and cardiovascular mortality as compared to DAPT [Our results have demonstrated that the use of SAPT is not significantly associated with higher rates of recurrent variceal bleeding ( to DAPT . HoweverP < 0.05). However, the only predictor of bleeding in cirrhotic patients on anticoagulation was a history of esophageal varices  and not the use of antiplatelet therapy , theorizing that increased bleeding in cirrhotic patients is due to pre-existing esophageal varices [Moreover, we could not assess the use and comparison of DAPT. A recent study reported that cirrhotics with acute MI on DAPT had significantly increased UGB compared to non-cirrhotics . This study also compared outcomes between SAPT and DAPT. Similar risks of gastrointestinal bleeding were identified from both DAPT and SAPT , with a significantly decreased all-cause mortality . There were no significant differences in all-cause mortality, recurrent MI, or bleeding, depending on the use of either Clopidogrel or Aspirin as SAPT . AdditioOur study has several limitations. Since this was only a single-center study, with small sample size, external validity may be compromised. Additionally, inherent limitations of the retrospective nature of the study are present, such as the accuracy of medical documentation and missing information. We were also unable to perform a regression analysis to demonstrate the risk factors responsible for the death of patients at index admission. Perhaps the most significant limitation of our study was that cardiac catheterization was not performed to assess the presence of occlusive CAD. Deferring PCI may have been attributed to the critical condition of patients at the time of Index admission, with the risk of potentiating variceal bleeding.In summary, we conclude that concomitant AVB and ACS is a severe disorder amongst cirrhotic patients, with a high mortality rate. Provided the patient survives the initial insult, the use of single anti-platelet agents does not seem to exacerbate the incidence of variceal bleeding on follow-up, given successful obliteration of varices is achieved using band ligation. Furthermore, we hope our study serves as the steppingstone for large prospective clinical trials and multi-centric studies, to help delineate the efficacy and risks of using antiplatelet agents for this life-threatening presentation of events.