COVID-19 has led to potential delays in liver cancer treatment, which may have undesirable effects on the prognosis of patients. We aimed to quantify the COVID-19 pandemic impact on the survival of patients with hepatocellular carcinoma (HCC) who underwent transarterial chemoembolization (TACE).  A retrospective study was conducted in patients with HCC who underwent TACE at a tertiary care center during the prelockdown (March to July 2019) and lockdown (March to July 2020) periods. Demographic data, tumor characteristics, functional status, and vital status were collected from the hospital medical records. The endpoints were TACE interval, treatment response, and survival after TACE. Cox proportional hazards regression determined the significant preoperative factors influencing survival. P=0.007). The trend suggested a significant decrease in patients with HCC in the repeated TACE group (−33.3%). After screening, 145 patients were included (prelockdown (n = 87), lockdown (n = 58)). There was no significant difference in the 1-month objective response rate between the prelockdown and lockdown groups . During follow-up, 56 (64.4%) and 34 (58.6%) deaths occurred in the prelockdown and lockdown groups, respectively (P=0.600). Multivariate analysis revealed no association between the lockdown group and decreased survival .  Compared to prelockdown, a significant delay occurred during the lockdown in repeated TACE treatments (76.7 vs. 63.5 days,  The impact of the COVID-19 pandemic on liver cancer care resulted in significant decreases and delays in repeated TACE treatments in 2020 compared to 2019. However, treatment delays did not seem to significantly impact survival. Coronavirus disease 2019 (COVID-19) was first reported in Wuhan, China, in late December 2019 and rapidly evolved into a global pandemic. As of April 17, 2022, the cumulative number of cases reported globally was over 500 million, and the cumulative number of deaths was over 6 million . The couOncology services for patients with cancer were reorganized, and courses of action were considered to balance delays in diagnosis or treatment against the risk of COVID-19. However, routine cancer care was postponed, which resulted in unintended consequences. This may have impacted long-term prognosis and survival outcomes in patients who missed cancer screenings and surgical intervention during this period. Moreover, the World Health Organization reported that in May 2020, 42% of 155 countries had partially or completely suspended cancer treatment and confirmed that the impact was global [An association between increased mortality and delayed treatment has been demonstrated in various types of cancers. A systematic review stated that an association was found between a delay of four weeks in cancer treatment and increased mortality in cancers of the bladder, breast, colon, rectum, lung, cervix, and head and neck . In hepaOur study aimed to evaluate the prevalence of therapeutic delays and characterize the impact of the COVID-19 pandemic on the survival of patients with inoperable HCC who underwent chemoembolization.This study complied with the standards of the Declaration of Helsinki and current ethical guidelines and was approved by the institutional ethics committee (REC No. 64-456-7-1). The requirement of obtaining informed consent for this study was waived by the institutional review board, and all data were analyzed anonymously.This retrospective cohort study was conducted in consecutive patients diagnosed with HCC who underwent transarterial chemoembolization (TACE) between March 1 and July 30, 2019, and during the same period in 2020 at a university-affiliated tertiary care referral center in southern Thailand. All eligible patients who underwent TACE from March 1, 2020, to July 30, 2020, were included in the lockdown group (after COVID-19). These patients were compared with similar patients who underwent TACE in the previous year in the prelockdown group (before COVID-19). The diagnosis of HCC was established using the AASLD criteria based on characteristic imaging features or histopathological confirmation . Tumor sWe obtained patient characteristics, clinical history, laboratory data, and imaging results at HCC presentation and treatment procedures from the electronic medical records. Variables of interest included age, sex, liver disease etiology, Child–Pugh class, BCLC stage, tumor burden, vascular invasion, number of TACE sessions, TACE interval, and length of hospital stay. Laboratory data at the pre-TACE session included alanine transaminase (ALT), aspartate transaminase (AST), bilirubin, albumin, platelet count, and alpha-fetoprotein (AFP).In all patients, the TACE procedure was performed under local anesthesia through the transfemoral route by two interventional radiologists, each with more than eight years of experience in HCC therapy. First, visceral angiography of the celiac and superior mesenteric arteries was routinely performed to assess vascular anatomy, tumor vascularity, and portal vein patency using a 5-F catheter. Second, we performed selective catheterization to the tumor-feeding hepatic arteries or in extrahepatic collaterals as distal as possible in each tumor lesion using a microcatheter of either a 1.7-Fr microcatheter  or 1.98-Fr tip microcatheter  over a 0.016-inch or a 0.018-inch guidewire. Subsequently, a mixture of 10–20 mg of mitomycin C  and 4–16 mL of iodized oil  was injected into the tumor for chemoembolization. The amount of anticancer-in-oil emulsion was determined by tumor size, number of nodules, and arterial supply to the tumor. Subsequently, the feeding artery was embolized using gelatin sponge particles. Finally, we completed the procedure when the tumor-feeding branch was completely obstructed, and tumor staining from digital subtraction angiography  completely disappeared.Enhanced computed tomography or magnetic resonance imaging was performed four weeks after TACE by experienced radiologists to assess the radiological tumor response according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria . DetaileThe first TACE interval was defined as the duration from the date of HCC diagnosis to the date of the initial TACE procedure. In patients undergoing repeated TACE, the TACE interval was classified as the duration from the date of the latest TACE or latest recurrent imaging (before study periods) to the date of the TACE procedure during the study periods (March to July 2019 and March to July 2020). First TACE delays were defined as 90 days from diagnosis to initial treatment. Repeated TACE delays were also defined as 90 days from the latest TACE or latest recurrent imaging to the date of the TACE procedure during the study periods. The 90-day cutoff value was selected as a clinically relevant time point based on prior literature , 15. We R software version 4.1.0. Continuous data are expressed as mean or median with a measure of dispersion (standard deviation and range), and comparisons were achieved using Student's t-test or the Mann–Whitney U test. Fisher's exact test was used to compare categorical data. Overall survival (OS) was calculated from the date of TACE to the date of patient death or the last follow-up date. Patient status at the end of each study period  was defined as alive or dead. Baseline clinical characteristics, tumor manifestations, and lockdown grouping affecting survival were initially assessed via univariate analysis. Subsequently, all prognostic factors with a P value ≤0.2 from the univariate analysis were entered into the multivariate Cox proportional hazards regression analysis. The model was refined by sequentially removing nonsignificant variables. P values <0.05 were considered statistically significant.Statistical analyses were performed using n = 8); absence of HCC mass (n = 5); history of spontaneous tumor rupture (n = 5); cotreatment with systemic therapies during TACE session (n = 3); and severe arterioportal shunt (n = 1). Subsequently, 240 patients were enrolled. Among them, 95 (39.6%) and 145 (60.4%) patients underwent the first TACE and repeated TACE procedures, respectively.A total of 262 patients with HCC treated with TACE between March and July 2019 and during the same period in 2020 at Songklanagarind Hospital in southern Thailand were included in this study. Twenty-two patients were excluded for the following reasons: incomplete follow-up data (n = 48) and prelockdown (n = 47) periods (n = 58) compared to the prelockdown period (n = 87), which represented a 33.3% reduction. Repeated TACE services dropped every month from March to July 2020: March (−29%), April (−50%), May (−33%), June (−22%), and July (−44%) (P=0.826) (P=0.007). First TACE delay and repeated delay >90 days in the lockdown group tended to be higher than the prelockdown group, but not significantly different .Initially, a similar number of patients who underwent the first TACE were examined during the lockdown ( periods . Howevery (−44%) . The meaP=0.826) . HoweverA total of 20 cases (13 in the repeated TACE group and 7 in the first TACE group) experienced delays in the TACE procedure of more than 90 days. The causes of TACE delay were reported as follows: 12 cases were delayed due to healthcare providers postponing the TACE procedure, 4 cases were delayed due to poor liver function, 3 cases were delayed due to delayed imaging or diagnosis, and 1 case was delayed due to patient noncompliance (transportation limitations).The basic characteristics of the recruited patients who underwent repeated TACE are summarized in Baseline characteristics were compared between patients who underwent repeated TACE in the prelockdown and lockdown groups . The meaP=0.908). BCLC stage migration was also not significantly different (P=0.438). During follow-up, 56 (64.4%) and 34 (58.6%) deaths occurred in the prelockdown and lockdown groups, respectively (P=0.600).The treatment responses of the two groups are shown in P=0.600) (P=0.600).The median OS time of the repeated TACE group was 16.5 months (95% CI 13.8–19.9 months). The median OS times in the prelockdown and lockdown groups were 15.8 months (95% CI 12.4–20.8 months) and 17.8 months (95% CI 13.8‒NA months), respectively. The cumulative survival rates between prelockdown and lockdown groups were not significantly different at 6 months (83% vs. 83%), 12 months (61% vs. 64%), and 18 months (45% vs. 48%) by the log-rank test (P=0.600) . The morP=0.013), albumin level ≤3.5 g/dL (P=0.001), size of main tumor >5 cm (P=0.012), number of tumors >5 (P  <  0.001), and presence of vascular invasion (P  <  0.001) were significant prognostic factors. Multivariate analysis for the potential prognostic factors affecting survival showed that albumin level ≤3.5 g/dL (hazard ratio (HR) 1.73, P = 0.016), number of tumors >5 , and presence of vascular invasion  were the only three independently significant prognostic factors associated with shorter survival. In univariate and multivariate analyses, the lockdown group and TACE interval >90 days were not significantly associated with decreased survival.Univariate and multivariate logistic regression analyses were used to determine the significant prognostic factors influencing survival . Among tn = 2), lockdown (n = 2)) had a diagnosis of an active COVID-19 infection. The patients were female in 75% of cases with a mean ± SD age of 58.5 ± 2.2 years. The diagnoses of these COVID-19 patients were based on PCR in three patients (75%). All four patients had only mild symptoms, such as fever, cough, or runny nose, and stayed in home isolation for 10 days. The medical treatment in these patients included an antibiotic regimen and antiviral therapy.Of the HCC patients in the repeated TACE group (145 patients) exposed to the pandemic, 2.8% (4/145) (prelockdown (n = 7), best supportive care (n = 7), and radiation therapy (n = 1). Failed or contraindicated TACE procedures were also a factor, with one patient experiencing unsuccessful tumor feeder catheterization and another patient having severe arterioportal shunting. Notably, no patients required modification to their TACE treatment due to COVID-19-related conditions.During the lockdown period, modifications were made to the TACE treatment during the follow-up period for a total of 17 cases (9 in the repeated TACE group and 8 in the first TACE group). The most frequent reason for modifying the treatment strategy was due to tumor progression, which required a switch to systemic therapy (P=0.007). In the multivariate analysis of patients undergoing repeated TACE, the lockdown group and treatment delay >90 days were not associated with increased mortality. Statistically significantly increased mortality hazards were observed in patients with albumin level ≤3.5 g/dL, number of tumors >5, and presence of vascular invasion.The current study showed a significant decrease in the number of repeated TACE procedures performed among patients diagnosed with inoperable HCC after the COVID-19 outbreak compared to the same period in the previous year. In our study of 262 patients with inoperable HCC, approximately one in seven patients experienced a first TACE delay and nearly one in four experienced a repeated TACE delay. A significant delay of approximately two weeks in repeated TACE procedures was observed in the lockdown group compared to the prelockdown group (76.7 vs. 63.5 days, The COVID-19 pandemic has had a significant impact on the delivery of cancer care, and our study highlights some of the challenges faced by HCC patients undergoing repeated TACE therapy. We observed a steep decrease in the number of patients receiving repeated TACE and a delay in the TACE interval time during the pandemic. Furthermore, a significant proportion of patients requiring TACE were not treated at all due to various factors such as postponed procedures, poor liver function, delayed imaging or diagnosis, and limited transportation. The reasons for this delay are multifactorial and include restrictions on hospital visits and triage of patients with COVID-19 infection risks to outdoor quarantine areas. Fear of contracting the virus also led to patient hesitancy in visiting hospitals. Additionally, the COVID-19 pandemic resulted in a shift in the primary attention of healthcare systems towards managing COVID-19 patients, causing routine services in oncology care to receive secondary attention and restricting access to these clinical services. It is important to consider the balance between decreasing the risk of COVID-19 infection and worsening cancer outcomes due to the absence of sufficient cancer treatment, which presents a healthcare ethical dilemma , 17. In We observed that nearly one in four patients experienced a repeated TACE delay. Treatment delays may be anticipated in patients with HCC given the potential changes in liver decompensation and tumor progression . SeveralAt least two sequential TACE procedures should be performed before treatment is abandoned due to a lack of tumor response . In a unLow albumin level, number of tumors >5, and presence of vascular invasion were independently associated with shorter survival on multivariate analysis, which was similar to the results of previous studies , 27–29. The strength of this study is the broad study population with indications for TACE. We included patients with HCC classified with BCLC stages A, B, and C that represented the real-life situation in middle-income countries. Additionally, we evaluated the impact of therapeutic delays in the lockdown group on prognosis consequences not only in radiological response but also on survival outcome. However, our study has some limitations. First, the number of patients in this series was relatively small in a single-center study, and the follow-up duration was relatively short. Second, other technical factors in selective TACE that were not assessed included the grading of portal vein visualization and the safety margin of iodized oil accumulation. Third, our study included only patients in a single institute in southern Thailand, which was mildly impacted by the COVID-19 pandemic. Therefore, the results may not be applicable to patients in areas with a higher prevalence of coronavirus infection.In conclusion, the COVID-19 pandemic had a significant impact on liver cancer care in southern Thailand, resulting in decreased and delayed delivery of repeated TACE in 2020 compared to 2019. Despite these treatment delays, survival rates for patients with inoperable HCC were not significantly impacted. While these findings do not recommend prolonging waiting times for TACE, a reasonable delay in chemoembolization based on tumor behavior and liver status in patients with HCC does not appear to increase the risk of death.


Postoperative delayed hyponatremia (PDH) is a major cause of readmission after endoscopic transsphenoidal surgery (eTSS) for pituitary adenomas (PAs). However, the risk factors associated with PDH have not been well established, and the development of a dynamic online nomogram for predicting PDH is yet to be realized. We aimed to investigate the predictive factors for PDH and construct a dynamic online nomogram to aid in its prediction.We analyzed the data of 226 consecutive patients who underwent eTSS for PAs at the Department of Neurosurgery in Jinling Hospital between January 2018 and October 2020. An additional 97 external patients were included for external validation. PDH was defined as a serum sodium level below 137 mmol/L, occurring on the third postoperative day (POD) or later.P = 0.033), prothrombin time (PT) , and percentage of monocytes  were identified as predictive factors for PDH via multivariable logistic regression analysis. Based on these predictors, a nomogram was constructed with great discrimination in internal validation (adjusted AUC: 0.613–0.688) and external validation (AUC: 0.594–0.617). Furthermore, the nomogram demonstrated good performance in calibration plot, Brier Score, and decision curve analysis. Subgroup analysis revealed robust predictive performance in patients with various clinical subtypes and mild to moderate PDH.Hyponatremia on POD 1–2 (OR = 2.64, Preoperative PT and the percentage of monocytes were, for the first time, identified as predictive factors for PDH. The dynamic nomogram proved to be a valuable tool for predicting PDH after eTSS for PAs and demonstrated good generalizability. Patients could benefit from early identification of PDH and optimized treatment decisions.The online version contains supplementary material available at 10.1186/s41016-023-00334-3. Management of pituitary adenomas (PAs) includes surgical resection, medications, and radiotherapy. Endoscopic transsphenoidal surgery (eTSS) is a common treatment approach for PAs. Postoperative delayed hyponatremia (PDH) occurs in 1.8–35% of patients who undergo eTSS . AdditioPrevious research has reported various predictors for PDH, including old age, serum sodium concentrations on postoperative days (POD) 1 and 2 , postopeIn this study, we aimed to thoroughly explore the predictive factors for PDH and further establish the first predictive dynamic online nomogram forecasting PDH after eTSS for PAs.This retrospective study included patients who underwent eTSS for PAs between January 2018 and October 2020 at the Neurosurgery Department of Jinling Hospital. Additionally, a total of 97 PA patients from The First Affiliated Hospital of Nanjing Medical University were included for external validation. The criteria for inclusion were as follows: (1) pathologically confirmed PA, (2) patients who underwent eTSS, (3) patients with laboratory assessment of serum sodium concentration on the POD 3 or later (outcome variable), and (4) patients with at least one collected variable. The exclusion criteria included: (1) PAs not confirmed by pathology, (2) patients without the outcome variable or patients who did not have any collected variables, and (3) patients with hyponatremia lasting from POD 1 and 2 to POD 3 or later.Our institutional research ethics board approved this retrospective study (2021NZKY-037–01) and waived the requirement for obtaining informed consent due to the retrospective nature of the research and data anonymization.Hyponatremia was defined as serum sodium concentration < 137 mmol/L based on the normal range of serum sodium concentration in our institution. There are many incidence time points for PDH in the literature. We defined PDH as hyponatremia occurring on POD 3 and onwards in the current study, as most studies included in Lee et al.’s meta-analysis applied this criteria , growth Patients will be transferred to intensive care unit (ICU) after operation. On POD 2, if their condition is stable, they will be transferred to general ward for further care. Input and output of patients are routinely recorded in ICU, and urine output will be monitored until discharge. In general, electrolytes levels, including serum sodium concentration, are monitored within 24 hours after operation and on POD 3 and 5 as well. If any abnormal items were detected, more intensive monitoring of electrolytes levels will be applied. For patients with mild hyponatremia, adjusted diet with more sodium salt will be recommended. In case of moderate to severe hyponatremia or corresponding symptoms, including nausea, vomiting, and changes in mental state, patients will be admitted with oral sodium supplementation or sodium intravenous infusion. Desmopressin will be used to treat patients with polyuria.N = 226)  guidance . Because logistic regression analysis was applied in the current study, continuous variables without normal distributions were either transformed into the logarithmic scale or recoded as binary variables. Interaction between collected variables were explored; however, no clinical meaningful interactions were detected. First, a comparison of variables was performed between groups with and without PDH. Student’s N = 156) was extracted and used to develop nomogram models with these 5 imputed datasets, respectively. Independent predictors were integrated and visualized as a nomogram model using the “rms” R package (version 6.1.0). The events per variable (EVP) = 10 criteria was used as the sample size estimation method for the current risk prediction model [www.shinyapps.io). The R software (version 3.6.0) was used for statistical analyses in the current research, and P < 0.05 and 0.1 were considered statistically significant and marginally statistically significant, respectively.Complete dataset  or marginal significance (P < 0.1).The origin datasets from training dataset were used to compare variables between patients with and without PDH. In the comparison, we filtered the variables with statistical significance , monocyte percentage, PT, international normalized ratio (INR), and chlorine. Conversely, patients without PDH had higher free triiodothyronine (FT3) and white blood cell (WBC) count.P < 0.05) or marginal significance (P < 0.1). The results showed that hyponatremia on POD 1–2, visual impairment, FSH, FT3, WBC count, monocyte percentage, PT, INR, and total bilirubin were identified as influencing factors for PDH , the percentage of monocytes , and PT  were identified as risk factors for PDH . The ability of the nomogram model to discriminate patients likely to develop PDH was assessed with AUC values from the ROC curve analysis.Based on the predictors revealed in the multivariable logistic regression analysis, three variables were integrated into the final nomogram , 0.650 , 0.689 , 0.668 , 0.670 , and 0.672  .Several predictors for PDH have been proposed. The predictive roles of age, gender, tumor type (functioning vs. nonfunctioning), and tumor size had been broadly discussed without any consistent conclusion . Pooled Lin et al. explored predictive value of the shape of pituitary, including diaphragma sellae sinking depth, the deviation angle difference of the pituitary stalk, and postoperative length of the “measurable pituitary stalk” . In the The following hypotheses have been proposed to explain the occurrence of PDH: syndrome of inappropriate antidiuretic hormone secretion (SIADH), cerebral salt wasting syndrome (CSWS), glucocorticoid deficiency, hypothyroidism, and medications , 24. HowP = 0.033; Table Previous studies have reported the predictive value of postoperative early sodium concentration for PDH. In a study conducted by Krogh et al., it was found that patients with PDH at POD 7 had significantly lower sodium levels during POD 1–2 . RajaratP < 0.05) [P = 0.039; Table Hypothyroidism was found to be a possible reason of hyponatremia by decreasing water delivery to the nephron, leading to increased free water retention and inhibiting its excretion . Tomita P = 0.007; Table P = 0.019; Table P = 0.047; Table To our knowledge, the current research was the first investigation into the potential relationship between immune-related factors and PDH after eTSS for PAs. Our results showed that patients with a lower WBC count . The potential mechanism between PT and PDH could be attributed to the fact that higher PT levels reflect poor coagulation function. This, in return, may lead to more challenging surgery, prolonged operation time, and more severe impairment of the pituitary stalk. The impairment of the pituitary stalk can restrict the transport and secretion of ADH, potentially leading to PDH. In the research conducted by Lin et al., they investigated the predictive role of postoperative measurable pituitary stalk length for PDH. They suggested that change of pituitary stalk and damage to it may result in abnormal secretion of ADH and subsequently lead to PDH [For the first time, our results showed that PT was an independent predictor of PDH  and after imputation (red line) show good imputation. Supplementary Figure 3. ROC analysis of the nomogram model and variables in the final model from the imputed dataset 1 (A), dataset 2 (B), dataset 3 (C), dataset 4 (D), and dataset 5 (E). AUC, area under the curve. Supplementary Figure 4. Calibration plots of the nomogram from the imputed dataset 1 (A), dataset 2 (B), dataset 3 (C), dataset4 (D), and dataset 5 (E). PDH, postoperative delayed hyponatremia. Supplementary Figure 5. Decision curve analysis with 95% confidence interval of the nomogram from the imputed dataset 1 (A), dataset 2 (B), dataset 3 (C), dataset 4 (D), and dataset 5 (E).


Acute myocardial infarction (AMI) is one of the leading causes of death worldwide, and approximately half of AMI-related deaths occur before the affected individual reaches the hospital. The present study aimed to identify and validate genetic variants associated with AMI and their role as prognostic markers.We conducted a replication study of 29 previously identified novel loci containing 85 genetic variants associated with early-onset AMI using a new independent set of 2,920 Koreans .LINC02005 and CNTN3, significantly increased longitudinal cardiac mortality and recurrent AMI. CNTN3 is known to play a role in altering vascular permeability. Another variant, rs78631167, located upstream of PLAUR and known to function in fibrinolysis, was moderately replicated in this study. By surveying the nearby genomic region around rs78631167, we identified a significant novel locus (rs8109584) located 13 bp downstream of rs78631167. The present study showed that six of the early-onset variants of AMI are applicable to both early- and late-onset cases.Of the 85 previously reported early-onset variants, six were confirmed in our genome-wide association study with a false discovery rate of less than 0.05. Notably, rs12639023, a cis-eQTL located in the intergenic region between Our results confirm markers that can potentially be utilized to predict, screen, prevent, and treat candidate patients with AMI and highlight the potential of rs12639023 as a prognostic marker for cardiac mortality in AMI. Acute myocardial infarction (AMI) is a leading cause of death worldwide, with more than one million deaths per year . ElucidaHere, we present a replication study of a GWAS using 1,173 new patients with AMI who were eventually treated with percutaneous coronary intervention (PCI) and 1,747 healthy controls from the Korean Genome Project . Moreovehttp://koreangenome.org). The genomes of these 1,173 patients were compared with those of 1,747 control subjects in Korea. Written informed consent was obtained from all participants in this study. Sample collection and sequencing were approved by the Institutional Review Board (IRB) of the Ulsan National Institute of Science and Technology (UNISTIRB-15-19-A). Analyses were performed using Python version 3.7.7 and R version 3.5.0.A total of 1,173 patients with AMI from the Chungbuk National University Hospital in Korea were enrolled, and 1,747 healthy individuals from the Korean Genome Project (KGP) were selected as controls , 6. Patiwww.bioinformatics.babraham.ac.uk/projects/fastqc/) software. Additional details regarding the genomic variant identification are provided in the WGS was performed using the MGI T7 platform, and clinical information from the KGP was matched. A total of 2,920 case and control samples were sequenced for this study in 2020. We filtered and finalized samples according to the following criteria: (i) Case: patients with AMI undergoing PCI surgery and (ii) control: healthy participants without AMI history or stent surgery. In total, 1,129 cases and 1,636 control samples were analyzed for further analysis . GenomicP-value threshold was determined to be 5.88 × 10−4 which is the same as 0.05 FDR value with Bonferroni correction. We assigned significantly replicated variants using the following criteria: (i) variants whose P-value was over the significance threshold, and (ii) variants that had a consistent direction of effect in both GWAS results between the discovery and replication datasets.GWAS was performed using logistic regression with an additive genetic model using PLINK (ver. 1.9b) . A totalSurvival analysis was performed using the Cox multivariate regression model to estimate the risk of composite outcomes of cardiac mortality and recurrent AMI among patients with AMI by genotype. The survival package in R software (ver. 4.2.2) was used for the analysis . Age andhttp://www.mulinlab.org/qtlbase) . Significant variants from the GWAS were queried for their dose-dependent genetic influence on various molecular phenotypes previously reported in the publicly available QTLbase database  . QTLbaseP < 5.88 × 10−4) . Another variant, rs12921822 , located in an intron of RNA binding fox-1 homolog 1 (RBFOX1), was also replicated. RBFOX1 is known to be involved in cardiomyopathy (MUC4), was significantly associated with AMI . MUC4 was reported to contribute to cancer progression by suppressing apoptosis and prompting tumor cell proliferation  exerting risk and protective effect on the occurrence of AMI, respectively.We found that six variants out of the 85 suggestive early-onset markers were significantly replicated in the AMI group using GWAS over a statistically significant false discovery rate (FDR) threshold  . Two intferation . Other tPLAUR) was moderately significant in this study . Although rs78631167 did not show a strong association in the new cohort, rs8109584 showed a significant association with AMI (P = 1.43 × 10−5), which is 13 bp away from rs78631167, indicating that the genetic block where these variants lie may have a relationship with AMI. PLAUR encodes CD87, which converts plasminogen to plasmin, resulting in clot lysis and plaque healing , such as eQTL (expression QTL), mQTL (methylation QTL), and tuQTL (transcript usage QTL), from the QTLbase (ver. 2.0), which accumulates information about molecular phenotypes and their QTLs to improve the biological interpretability of genetic markers  on longitudinal cardiac mortality and recurrent AMI  > 1] on longitudinal cardiac mortality and recurrent AMI when the survival associations between the variants and cardiac mortality were analyzed using longitudinal follow-up data after PCI in individuals with AMI . Among trent AMI .This study aimed to identify replicated genetic variants of AMI from 85 previously reported variants associated with early-onset AMI using a new set of 2,920 Koreans. The new independent replication dataset consisted mainly of patients with late-onset AMI. We hypothesized that there are markers that are applicable to both stages or types of AMI. Nonetheless, our sample size including 1,747 healthy controls is still relatively small.PLAUR, had a modest effect (P = 1.58 × 10−3). Moreover, rs8109584, located 13 bp downstream of rs78631167, was significantly associated with AMI (P = 1.43 × 10−5), suggesting that the genetic block located upstream of PLAUR is significantly associated with AMI.Among the variants related to the four major mechanisms previously mentioned for early-onset AMI , a fibriLINC02005 and CNTN3, showed the highest enhancing effect on longitudinal cardiac mortality and recurrent AMI expression. It is also a cis-eQTL that increases the expression of CNTN3 encoding contactin 3 (The results of the present study propose that vascular permeability could serve as a crucial mechanism for predicting the occurrence and prognosis of AMI. Of the significantly replicated variants, rs12639023, located near tactin 3 . Notablytactin 3 , 16. Eletactin 3 . Howevertactin 3 . NonetheThe two key strengths of our study include clearly defined sample collection and replication of genetic markers using thousands of samples in an independent cohort. While most studies have used patients with AMI with heterogeneous phenotypes , 23, theOur study has two limitations. First, this study was conducted in patients with AMI of Korean ancestry. These results should be validated in populations of multiple races. Second, this study confirmed the replication of AMI-associated variants in a small sample size of 2,920 individuals. While significant variants were observed not in the replication but in the discovery phase, rs8109584, which is 13 bp away from rs78631167, was significantly found in the replication rather than the discovery phase. It is necessary to increase the sample size to ensure validation.In conclusion, this study confirmed the replication of six genetic variants associated with AMI by using GWAS, QTL mapping, and survival analyses. Our findings highlight the potential of rs12639023 as a prognostic marker for cardiac mortality in AMI. These results provide insights into the latent etiology of AMI. The replicated genetic variants are potential biomarkers for the prediction, prevention, prognosis, and personalized treatment of AMI in individuals who carry the variant. They could be clinically utilized in routine health check-ups to assess the risk of AMI by a genetic risk score derived from these variants, enabling the early prediction of individuals with a higher genetic predisposition for AMI.


Staphylococcus aureus (MRSA) bacteremia is a major concern in the global healthcare system. However, data from Asian regions dealing with the singularity of this infection in older persons is lacking. We aimed to identify the differences in the clinical characteristics and outcomes of MRSA bacteremia between adults aged 18–64 and ≥ 65 years.Methicillin-resistant A retrospective study cohort was conducted at the University Malaya Medical Centre (UMMC) on cases of MRSA bacteremia from 2012 to 2016. Patient demographic and clinical data were collected for risk factors analyses.New cases of MRSA bacteremia showed a trend of increase from 0.12 to 100 admissions in 2012 to 0.17 per 100 admissions in 2016 but a drop was observed in 2014 (0.07 per 100 admissions). Out of the 275 patients with MRSA bacteremia, 139 (50.5%) patients were aged ≥ 65 years old. Co-morbidities and severity at presentation were significantly higher among older adults, including diabetes mellitus (p = 0.035), hypertension (p = 0.001), and ischemic heart disease (p < 0.001), as well as higher Charlson Comorbidity Index (p < 0.001) and Pitt bacteremia scores (p = 0.016). Central line-associated bloodstream infections were more common among younger patients , while skin and soft tissue infections are more frequent among older adults . All-cause mortality and in-hospital mortality were significantly higher in older patients . Multivariate analysis revealed age ≥ 65 years , Pitt score ≥ 3 , hospital  and healthcare  acquisition of MRSA, indwelling urinary catheters , inappropriate targeted treatment , lack of infectious disease team consultation  and hypoalbuminemia , were significant risk factors for 30-day mortality.Older patients’ risk of mortality from MRSA bacteremia was three times higher than younger patients. Our data will contribute to developing and validating a robust scoring system for risk-stratifying patients to achieve better management and improved clinical outcomes. The global population aged 65 years and above has increased from 7.6 to 9.3% within the past decade . By 2050Staphylococcus aureus is a Gram-positive bacterium that colonizes the nares, axillae, vagina, pharynx, and damaged skin surfaces. S. aureus has been identified as an important etiologic agent of nosocomial infections [S. aureus usually leads to just minor skin infections  [S. aureus is often associated with high morbidity and mortality [fections . While Sculitis) , penetraculitis) . Even wiortality .S. aureus is essentially classified into two groups based on antibiotic susceptibility: methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) [S. aureus bacteremia cases and is often associated with higher mortality rates and poorer clinical outcomes compared to MSSA [s (MRSA) . MRSA ins (MRSA) . In 2019s (MRSA) . Asia res (MRSA) . When its (MRSA) , 12. MRS to MSSA . Given tThis study aims to determine the differences in clinical characteristics and outcomes of MRSA bacteremia between patients aged 18–64 years and those aged 65 years and over and to identify factors associated with increased risk of infection. The findings of this study will inform future epidemiological, clinical and molecular studies to guide the development of evidence-based management of MRSA bacteremia.This retrospective observational study cohort was conducted at the University Malaya Medical Centre (UMMC), a tertiary teaching hospital located in Kuala Lumpur, Malaysia. Ethics approval was obtained from the UMMC medical research ethics committee (MEC-ID: 20145-168). Consecutive patients who had MRSA isolated from blood cultures taken between 1st January 2012 to 31st December 2016 were identified from the Medical Microbiology Diagnostic Laboratory database. All adult patients (aged 18 years and older) with MRSA bacteremia during this period were included. A standardized case report form was used to collect all required data extracted from patient case notes (for cases between January 2012 – September 2014) and the hospital electronic medical records (for cases from October 2014 onwards). Demographic and clinical data collected included age, sex, ethnic origin, co-morbidities, length of hospital stay, source of acquisition , site of infection, previous antibiotic use, principal clinical manifestations, presence of indwelling devices, source control, antibiotic treatment, follow-up, and outcomes at 14 days, 30 days, 90 days, and 6 months after first positive culture, relapses, and recurrences of MRSA bacteremia.The MRSA bacteremia cases/100 admissions were calculated using the total adult admissions for the respective years as the denominator. Co-morbidities and severity of sepsis were measured by the Charlson Comorbidity Index  and PittIndividuals who had MRSA identified from at least one blood culture with or without clinical signs and symptoms of infection were identified. The sources of MRSA acquisition were categorized according to the Friedman criteria : hospitaS. aureus from two or more blood cultures in a patient who had a central line at the time of infection or within 48 h before the development of infection. Surgical site infection (SSI) was defined based on the CDC criteria [The bacteremia sources were defined according to the Centre for Disease Control and Prevention (CDC) criteria . Brieflycriteria . Cathetecriteria .Empirical antibiotic use was affirmed if administered after the onset of symptoms but before microbiological information was obtained. Initial antibiotic treatment was considered appropriate if the strain was susceptible to at least one of the antibiotics administered according to the Clinical and Laboratory Standards Institute (CLSI) breakpoints during the time of analysis except for aminoglycosides, which were considered inappropriate regardless of the susceptibility test results .The management strategies employed include the request for a transthoracic or transesophageal echocardiogram , the number of repeat cultures obtained every 72 h until culture negative, removal of implanted prostheses and/or catheters, initiation of an antimicrobial agent with activity against MRSA and duration of treatment was recorded . DefinitThe outcomes recorded include persistent and recurrent bacteremia, mortality, and length of stay. Persistent was defined as bacteremia of 7 days or longer despite optimal treatment . RecurreAll statistical analyses were performed using SPSS version 25 . Baseline data including patients’ demography, clinical characteristics, disease severity, and clinical and treatment outcomes were compared between patients aged 18 to 64 years and those aged 65 years and above. Continuous variables were represented as mean ± standard deviation (SD) and compared using the Student t-test. Categorical variables were represented as count (n) and frequency (%) and compared using the Chi-squared or Fisher’s exact test, as appropriate. Statistical significance was established at p < 0.05. All variables were included in a multiple regression analysis to determine the significant predictors of early (14-day) and 30-day mortality. The risk factors, or factors associated with mortality, were expressed as adjusted odds ratios (AOR) with 95% confidence intervals (CI). Survival probabilities at 14, 30, and 180 days were compared between the two age groups using the Log-rank test. A Kaplan-Meier survival curve was plotted to compare the cumulative survival of the two age groups at three and six months.A total of 275 unique cases of MRSA bacteremia were identified between 2012 and 2016. Table Approximately half of the patients  were aged 65 years and older. Male patients  were more represented than female patients . Most of the patients were of Malay  and Chinese  ethnicities, followed by Indians  and others . The average length of hospital stay was 24.2 days with a 19.3% ICU admission rate. Most of the patients were previously hospitalized (88%) with the majority of them reporting a recent hospitalization . More than half of the MRSA bacteremia cases were associated with HA infections (52.7%), followed by HCA (35.6%) and CA (11.6%) infections. Approximately 66.3% of the patients with HCA infection had been previously admitted to UMMC.Enterococcus faecalis (n = 12), pan-susceptible Acinetobacter baumannii (n = 8), pan-susceptible Klebsiella pneumoniae (n = 13), and Enterococcus faecium (n = 7).A comparison of patients’ demography and clinical characteristics between age groups revealed significant differences in ethnicity (p ≤ 0.001), more common use of continuous bladder drainage (p = 0.003), and other devices  tube, prosthetic valve, pacemaker, prosthetic implants, or cerebral shunts) (p = 0.016), and higher rates of diabetes mellitus (p = 0.035), hypertension (p = 0.001), and ischemic heart disease (p < 0.001) among the older patients Table . SimilarTable All variables including patient demographic data, clinical characteristics, disease severity, treatment, and clinical outcomes were assessed to determine the risk factors for early 14-day) and 30-day mortality in the patients with MRSA bacteremia. Multivariate analysis revealed that old age (≥ 65 years old), infections caused by HCA-MRSA, hypoalbuminemia (< 29 g/L), and inappropriate targeted treatment for MRSA bacteremia were significantly associated with 30-day mortality  when measured across three different time points  Table . The KapIn this study, MRSA bacteremia was mainly acquired in the hospital (52.7%) and other healthcare facilities (35.6%). Similar observations were noted in other countries in Southeast Asia , 27. Ouraureus bacteremia is higher in the older population [Infections in older persons accounted for over half of the cases of MRSA bacteremia identified in this study. Previously conducted epidemiological studies showed that S. pulation , 33. Ourpulation , 32. Mulpulation –38.S. aureus is not typically considered a major cause of UTI, recent epidemiological studies indicate that S. aureus is an emerging cause of UTI in specific patient populations, such as pregnant women and those with complicated UTI [The presence of an indwelling urinary catheter was significantly associated with mortality in patients with MRSA bacteremia in this study. Indwelling urinary catheterization poses serious complications and increases the risk of bloodstream infection in older patients , 39. Preated UTI . Previouated UTI . This shated UTI .We observed that the rate of CLABSI was significantly higher in younger patients in this cohort. This is likely due to the higher number of younger patients (26.6%) having central venous catheters (CVC) compared to older persons (18%). The high rates of CLABSI in both groups may be attributable to the suboptimal compliance to central line care bundles leading to an increased introduction of infection during insertion and manipulation of the lines . In thisConsistent with previous reports, the Charlson Comorbidity Index and Pitt bacteremia scores were observed to be higher in older patients , 49. AntPrevious studies have highlighted the relationship between inappropriate empirical therapy with increased mortality , 53. TheIn the present study, approximately one-third of the older patients received ID consultations. The mortality risks on days 14 and 30 were six and three times higher in patients who did not get an ID team input compared to those who did. Similarly, studies by Buehrle et al.  and PragThere are several limitations to our study. Firstly, this is a single-center study hence the findings might not represent the entire population and the retrospective nature of this study is subjected to the potential effects of unmeasured variables, missing information, selection and recall biases . SecondlThe incidence of MRSA bacteremia in healthcare settings is higher than in the community. Older age, higher Pitt bacteremia scores, HA-MRSA and HCA-MRSA, hypoalbuminemia, polymicrobial infection, presence of indwelling urinary catheters, lack of ID team consultation, and inappropriate targeted treatment were the significant risk factors for mortality in MRSA bacteremia. Older patients had a three times higher mortality risk than younger patients. Specific policies and guidelines for the prevention and management of MRSA bacteremia are urgently needed to address the rising rates of infection as well as to improve outcomes, particularly in older patients.


Histological evaluation by liver biopsy is considered the gold standard for assessing liver disease; however, it is highly invasive. Non-invasive liver stiffness measurement by shear wave elastography (SWE) is effective for evaluating the hepatic fibrosis stage and related diseases. In this study, we investigated the correlations of liver stiffness with hepatic inflammation/fibrosis, functional hepatic reserve, and related diseases in patients with chronic liver disease (CLD).Shear wave velocity (Vs) values were measured using point SWE in 71 patients with liver disease from 2017 to 2019. Liver biopsy specimens and serum biomarkers were collected at the same time, and splenic volume was measured using computed tomography images with the software Ziostation2. Esophageal varices (EV) were evaluated by upper gastrointestinal endoscopy.P < 0.01). Comparison of ROC curves to predict EV showed that the AUROC for Vs values was 0.901, which was significantly higher than the AUROCs for FIB-4 index (P < 0.05), platelet count (P < 0.05), M2BPGi (P < 0.01), hyaluronic acid (P < 0.05), and splenic volume (P < 0.05). In patients with advanced liver fibrosis (F3 + F4), there was no difference in blood markers and splenic volume, while Vs value was significantly higher in patients with EV (P < 0.01).Among CLD-related function and complications, Vs values were highly correlated with liver fibrosis and EV complication rates. The median Vs values for liver fibrosis grades F0, F1, F2, F3, and F4 were 1.18, 1.34, 1.39, 1.80, and 2.12 m/s, respectively. Comparison of receiver operating characteristic (ROC) curves to predict cirrhosis showed that area under the ROC (AUROC) curve for Vs values was 0.902, which was not significantly different from the AUROCs for the FIB-4 index, platelet count, hyaluronic acid, or type IV collagen 7S, while it was significantly different from the AUROC for mac-2 binding protein glycosylation isomer (M2BPGi) (Hepatic shear wave velocity was highly correlated with EV complication rates in chronic liver diseases as compared to blood markers and splenic volume. In advanced CLD patients, Vs values of SWE are suggested to be effective in predicting the appearance of EV noninvasively. Chronic liver disease (CLD) is a major public health problem, accounting for significant morbidity and mortality worldwide , 2. CirrIn recent years, non-invasive tests have become an area of research in liver disease , 7. SheaIn this study, we investigated the correlations of liver stiffness measured by point SWE (pSWE) with hepatic inflammation/fibrosis stage, functional hepatic reserve, and portal hypertension-related complications in patients with CLD. Not only did pSWE values correlate with the stages of fibrosis assessed by liver biopsy and non-invasive tests such as serum biomarkers and splenic volume, but interestingly, the values were highly correlated with the appearance of esophageal varices (EV) in patients with advanced fibrotic liver diseases.We reviewed data of 71 patients with liver disease who underwent blood biochemical tests, assessment of shear wave velocity (Vs) using SWE, and liver biopsy at the Fukui University Hospital between April 2017 and March 2019. The background data of the patients are summarized in Table Abdominal ultrasonography was performed using Hitachi HI VISION Ascendus  to estimate the shear wave measurement (SWM). Within a single SWM measurement, several push track sequences are delivered, and the SWM samples Vs in multiple positions at different depths within the region of interest (ROI). This is automatically repeated within a short time (< 1 s). Based on the acquired SWM, the system displays a histogram and overview. The distribution of Vs is displayed in the histogram, interquartile range (IQR), depth of the sample, median Vs (m/s), and transformed kPa. This method has a built-in feature, the VsN, which is the reliability index of the Vs acquired per measurement and functions as a quality indicator; it ranges from 0–100% , 14. In Liver biopsy specimens were obtained percutaneously from the right lobe of the liver using a 16G or 18G biopsy needle under ultrasound guidance. Tissue samples were fixed in formalin, embedded in paraffin, and stained with hematoxylin–eosin, Masson’s trichrome, and Azan stains. A pathologist evaluated the specimens histologically. Liver fibrosis was staged according to the new Inuyama classification .Endoscopy was performed within one year before and after the date of SWE. Upper gastrointestinal endoscopy was performed using GIF-H290Z  endoscope. The endoscopic findings of EVs were evaluated according to the grading system outlined in the General Rules for Recording Endoscopic Findings of Esophagogastric Varices (2nd edition) prepared by the Japan Society for Portal Hypertension .3/mm3] × ALT [IU/L]1/2)  × AST [IU/L]) / (platelets [10U/L]1/2) .Splenic volume was measured using the commercially available software Ziostation2 . The spleen identified on the computed tomography (CT) images was reconstructed in three dimensions with Ziostation2, and the spleen volume was calculated.P < 0.05. Statistical analyses were performed using Prism software  and EZR software program . Youden's index (sensitivity + specificity—1) was used to identify the optimal cutoff point.One-way analysis of variance, receiver-operating characteristic (ROC) curve analysis, and Mann–Whitney’s U test were used to evaluate the results. Correlations were evaluated using Spearman's rank correlation coefficient. Statistical significance was defined as Vs value was measured with pSWE, and liver biopsy specimens were collected from 71 patients with liver disease and investigated for correlation with function and complications associated with CLD . The optimal cutoff value of Vs based on Youden index was 2.00 with a sensitivity of 85.3% and specificity of 90.0%  , platelet count (P < 0.05), M2BPGi (P < 0.01), hyaluronic acid (P < 0.05) and splenic volume (P < 0.05). The optimal cutoff value of Vs based on Youden index was 2.08 with a sensitivity of 80.0% and specificity of 85.4%. These results showed that Vs is highly useful for predicting EVs.Of the 45 patients who underwent upper gastrointestinal endoscopy, EVs were identified in 10 patients (Table 01) Fig. ; the AURWe next evaluated factors reflecting the presence of EVs in patients with histologically advanced liver fibrosis (stages F3 and F4). The Vs values were significantly higher in the group with EVs than that in the group without EVs -SWE is more useful in predicting liver fibrosis than FIB-4 index and M2BPGi [. reported that pSWE is more useful in predicting liver fibrosis than FIB-4 index and aspartate aminotransferase to platelet ratio index (APRI) [In the hepatic inflammation/fibrosis stage, functional hepatic reserve, and portal hypertension-related complications in patients with CLD, Vs values measured by pSWE were highly correlated with liver fibrosis and the complication rate of EVs. Vs values increased with the progression of liver fibrosis and tended to be a better predictor of cirrhosis (F4) than blood markers of liver fibrosis. Moreover, the diagnostic ability of Vs in predicting EVs was superior to blood markers and splenic volume. In advanced liver fibrosis patients, there was no difference in blood markers and splenic volume, while Vs value was high in patients with EVs.pSWE has been reported to be useful in diagnosing liver fibrosis caused by hepatitis B virus (HBV), hepatitis C virus (HCV), non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, and autoimmune hepatitis (AIH) –22. Numad M2BPGi . Park etx (APRI) . The reax (APRI) . These rx (APRI) –27.. reported for the first time that liver stiffness measured by SWE is useful in predicting EVs using the Acuson S2000  [. reported that liver stiffness is closely and directly correlated with HVPG [In predicting the presence of EVs, correlation with blood tests, especially platelet counts and liver fibrosis markers, has been reported . HoweverGermany) . Since tGermany) –32. PortGermany) , Carriónith HVPG . In patiith HVPG , which s. reported that the spleen size measured by ultrasound examinations was not superior to liver stiffness in the diagnosis of CSPH and varices [In this study, liver stiffness correlated with histological liver fibrosis and esophageal varices compared to splenic volume. Many studies suggested that the diagnostic value of spleen elasticity for high-risk varices (HRV)/ clinically significant portal hypertension (CSPH) is superior to liver elasticity , 36. Mea varices . In pati varices  and has  varices , 41. The. also reported that the diagnostic performance of SWE for liver fibrosis differs for each etiology of liver disease [There are several limitations to this study. First, the sample size was small. One of the aims of this study was to assess the significance and correlation of pSWE in patients with the chronic liver disease based on a histological assessment of the degree of liver fibrosis and inflammation. The usefulness of pSWE has been assessed in cases in which a liver biopsy, the gold standard to assess the nature and severity of liver disease, was performed, but the number of cases was therefore limited. Second, this study was conducted at a single institution. Third, the pathogenesis of CLD is heterogeneous, which is likely to affect the relationship of pSWE values to fibrosis or EVs. Herrmann et al disease , and theThe hepatic shear wave velocity of pSWE is highly correlated with liver fibrosis and the complication rate of EVs in patients with CLD. Furthermore, in patients with advanced liver fibrosis, the Vs value was more accurate than blood markers and splenic volume in predicting EVs. In patients with CLD, a non-invasive test using Vs values of pSWE was suggested to be useful as a screening test for predicting cirrhosis and EVs.


To investigate the complete clinical spectrum of individuals with paediatric tuberous sclerosis complex in southern Sweden and explore changes over time.In this retrospective observational study, 52 individuals aged up to 18 years at the study start were followed-up at regional hospitals and centres for habilitation from 2000 to 2020.Cardiac rhabdomyoma was detected prenatally/neonatally in 69.2% of the subjects born during the latest ten years of the study period. Epilepsy was diagnosed in 82.7% of subjects, and 10 (19%) were treated with everolimus, mainly (80%) for a neurological indication. Renal cysts were detected in 53%, angiomyolipomas in 47%, astrocytic hamartomas in 28% of the individuals. There was a paucity of standardized follow-up of cardiac, renal, and ophthalmological manifestations and no structured transition to adult care.in utero due to the presence of a cardiac rhabdomyoma. This allows for preventive treatment of epilepsy with vigabatrin and early intervention with everolimus for potential mitigation of other symptoms of tuberous sclerosis complex.Our in-depth analysis shows a clear shift towards an earlier diagnosis of tuberous sclerosis complex in the latter part of the study period, where more than 60% of cases showed evidence of this condition already  TSC1 or TSC2, which cause upregulation of the mechanistic target of rapamycin1 (mTOR1) signalling pathway [TSC1 or TSC2 variant, or both [Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder with almost complete penetrance that affects multiple organ systems . The est pathway . In TSC, pathway . TSC canIn the last few decades, TSC diagnostics, treatment, and surveillance have advanced markedly , 5. For Focal seizures and infantile spasms often occur in the first year of life , 4 and eWe reviewed the complete TSC clinical spectrum in a Swedish paediatric cohort and investigated changes in diagnostics and treatment over the last two decades. To our knowledge this is the first not registry-based retrospective study of all TSC manifestations in the modern era.All individuals younger than 18 years at the beginning of, or who were born during the study period (January 2000 to December 2020), fulfilling TSC diagnostic criteria, and followed up at the hospitals and centres for habilitation of children and adolescents in southern Sweden , were included. Collected data included demographics, family history of TSC, genetics, clinical manifestations, radiological findings, and treatment. Medical records were reviewed by specialists in the respective areas.Available echocardiographs and electrocardiograms (ECG) were reviewed for cardiac rhabdomyomas (CRs) and arrhythmias, respectively. The largest CR diameter on the earliest echocardiographic examination was recorded.From brain images, taken from radiology reports, we recorded cortical tuber, subependymal noduli, SEGA, and hydrocephalus data. The earliest scans were obtained by computed tomography (CT), which was later replaced by magnetic resonance imaging (MRI). SEGA was defined as a caudothalamic groove lesion with a size > 1 cm in any direction, or any subependymal lesion that showed growth on serial imaging, regardless of size . DRE wasIntellectual disability (ID) and neuropsychiatric (NP) disorders were diagnosed using standard psychological testing material. Non-NP linguistic problems were noted. Motor impairment was judged by physiotherapists.Renal imaging data were taken from the radiology reports and presence of AML and cysts recorded. First and last available creatinine values, urine dipstick results, and blood pressure, if two or more values were available, were recorded. Hypertension was defined as systolic and/or diastolic blood pressure ≥ 95th percentile for sex-, age-, and height-matched children.Ophthalmological records were reviewed for fundus appearance, electroretinography (ERG), and cerebral visual impairment (CVI). Due to the large spread in age at last available ophthalmologic examination, visual acuity was not compared, as the visual system is not fully developed in growing children.U test for continuous variables and Pearson Chi-square or Fischer´s exact test, as applicable, for two dichotomous variables. The level of significance was set at p < 0.05.Data were managed using the Research Electronic Data Capture database hosted by Lund University, Sweden, and were analysed using SPSS v27 software . Data are presented as median and range. Differences between groups were assessed by the Mann–Whitney The study was approved by the Swedish Ethical Review Authority and performed in accordance with the declaration of Helsinki.Characteristics and genetic findings of study individuals are presented in Table In the total cohort, CRs were detected in 77.5% 31/40) of the individuals, of which 38.7% 12/31) involved prenatal detection. As a feature leading to early diagnosis, CRs were significantly more often found in individuals born during 2010–2020 than in those born during 1983–2009 (p = 0.001)  inflow. He received a Blalock–Taussig shunt at 3 days old, which was catheter-closed at 11 months, due to CR regression and pulmonary over-circulation. Another boy had an intrauterine diagnosis of cardiac tumours and supraventricular tachycardia (SVT). A postnatal ECG displayed pre-excitation and SVT and he was treated with digoxin until 1 year old. The largest tumour obstructed RV outflow, necessitating surgical resection at age 1 week. Most CRs underwent spontaneous involution, but at least one remained detectable by 18 years old. Ventricular function was affected in two new-borns: in one, tumour masses occurred in both ventricles and filled the RV, although not necessitating any operative or medical treatment.Cortical tubers and subependymal nodules were found in 49 and 48/51 subjects (1/52 did not undergo CT or MRI). One individual that showed tubers, but not subependymal noduli, exhibited a mild phenotype with skin lesions and retinal astrocytic hamartomas, without clinical signs of neurological disease.SEGA was identified in 16/51 31.4%) individuals. Surgical treatment was performed in four and everolimus treatment was used in seven individuals  had an epilepsy history. Median age at seizure onset was 11 months (range 2–85 months). Twenty-three individuals developed epilepsy before the age of 1 year, of which 15 had infantile spasms. EEG showed hypsarrythmia in 12/15 individuals. Focal seizures were present 1–8 months before infantile spasm onset in 3/15 patients. These spasms developed to seizures with focal onset, either directly, or after a spasm-free period, with a semiology related to the seizure-onset zone. Three individuals had absences and drop attacks suggestive of Lennox–Gastaut syndrome.Of all individuals with epilepsy, 27/43 (62.8%) had DRE in at least one age-span Table . Among tThere was no statistically significant difference between those born 1983–2009 and 2010–2020 regarding age of first seizure (p = 0.214), number of patients with infantile spasms (p = 1.0), or number of patients with DRE < 5 years of age (p = 1.0).Two individuals with West syndrome responded to corticosteroids and nine to vigabatrin treatment. In 1/12 individuals with hypsarrythmia, treatment was unknown. Focal seizures were treated with the following drugs, either alone or in combination: carbamazepine (n = 12), clobazam (n = 11), clonazepam (n = 7), everolimus (n = 10), gabapentin (n = 2), lamotrigine (n = 20), levetiracetam (n = 19), oxcarbazepine (n = 23), perampanel (n = 2), phenobarbital (n = 5), pyridoxin (n = 6), sulthiame (n = 5), topiramate (n = 17), valproic acid (n = 29), vigabatrin (n = 24), and zonisamid (n = 3). Twelve individuals with previous epilepsy were seizure-free at study inclusion, four had discontinued their ASD, and two patients were on monotherapy. In a few individuals, vagus nerve stimulation (n = 2) or ketogenic diet (n = 1) were added, with a marked response. Twelve individuals became seizure-free on ASD monotherapy for more than 2 years. One individual became seizure-free with only a ketogenic diet.During 2011–2020, 8/10 individuals were treated with everolimus due to neurological indications Table , the youFrom 2013, 6/7 individuals with a neonatal TSC diagnosis were followed-up with regular EEG .Normal cognitive function was observed in 23/52 (44%) individuals. Thirteen showed mild, 14 moderate, and two severe ID. Attention deficit disorder (ADHD) was mild in seven and moderate in three, and autism was mild to moderate in 13, and severe in seven. Language impairment, not attributed to ID, autism, or ADHD, was reported in seven individuals, and was severe in two. Neuropsychiatric and cognitive symptoms, collectively known as TAND, were very common in our cohort, but was rarely formally reported in the patient chart. Motor impairment was recognised in 11 (22%) individuals.An ordinary school program was attended or finished by 23 , 20 (38%) were in special schools for individuals with ID, two (4%) had not started school, and data were missing for seven (13%).Appropriate renal imaging was available for 49/52 individuals. Eleven individuals underwent repeat ultrasound (US) examinations, and the remaining individuals underwent both US and MRI or occasionally CT and urography. Median follow-up was 4.83 years (0.25–16.67 years). Median renal lesion-detection age for individuals born during 2010–2020 was 4 months vs. 116 months for those born 1983–2009  individuals. These were single in three, multiple unilateral in four, and multiple bilateral in the remaining individuals. Two individuals underwent embolization of asymptomatic large AMLs before everolimus introduction. In one girl, everolimus treatment significantly reduced AML size, as well as multiple small renal cysts. The effect on renal manifestations in individuals treated with everolimus for neurological indications is presented in Table 7% indiviTSC2/PKD1 was found in one individual, who presented with renal cysts at age 6 months, hypertension at 14 months, and developed a clinical course akin to autosomal dominant polycystic kidney disease. Everolimus treatment was initiated at age 14 years, due to suspicion of AMLs, but was discontinued because of side effects and uncertain benefits. She developed end-stage renal disease and underwent successful kidney transplantation at age 17.5 years. The right kidney removed on this occasion contained multiple AMLs.Renal cysts were detected in 26 (53%) individuals: these were single in five, multiple unilateral in one, and multiple bilateral in the remainder. Contiguous deletion of Eleven individuals (22.4%) exhibited both renal cysts and AMLs. Small hyperechoic lesions in six individuals, considered as AMLs on US by a radiologist, were interpreted as renal cysts on MRI. In all eight individuals with CRs identified prenatally, renal lesions were detected during the first year of life. Small lesions could not be defined in 3/5 individuals who underwent US during the first month of life. Follow-up investigations showed renal cysts in all these individuals.TSC2/PKD1 deletion was diagnosed with hypertension and decreased kidney function. Urinalysis was available in 15 (28.8%) individuals. Intermittent microscopic haematuria was found in four , and proteinuria in one. No proteinuria was found in individuals treated with everolimus.Kidney function tests were available for 37 (71%) and blood pressure measurements for 17 (32.6%) individuals. Only the individual with the Renal data were available for 22/25 individuals at 18 years. Ten individuals were transferred for follow-up care under an adult urologist or nephrologist, four to primary care, and two to a neurologist. One individual without renal manifestations was transferred to primary care while the remaining five had no planned follow-up.One individual with renal cysts had hepatic cysts. AMLs in both the kidneys and the liver were detected in three individuals. One patient had suspicious, non-defined liver lesions.Ophthalmological records were available for 50 individuals. At the last registered ophthalmological examination, the median age was 13 (range 1.3–29.7) years. Astrocytic hamartomas in one or both eyes were detected in 16/50 (32%) individuals, and achromatic patches in 4/50 (8%). One individual developed a growing opticus astrocytoma necessitating eye enucleation, and optic atrophy because of SEGA growth. Vigabatrin treatment was used in 23/52 (44.2%). Full-field ERG was performed in 10 patients. Reduced ERG response was measured in 3/10, resulting in medication reduced or cessation. Some recovery was observed at follow-up examination. No individual was investigated for cerebral visual impairment.In many cases, skin manifestations were not documented in detail in medical records and therefore only treatment is presented. Before age 18 years, 11  had laser therapy and 11  were prescribed topical rapamycin for facial angiofibromas. Of these, six  underwent both treatments.No lung manifestations were reported in this cohort.As the presenting feature suggestive of TSC, CRs were significantly more commonly detected in individuals born during 2010–2020 than during 1983–2009. A low neonatal diagnostic frequency of CRs in the late nineteen-nineties and early two-thousands has been published previously . A CR waCRs are usually asymptomatic, but may cause severe morbidity requiring surgical intervention , as expeThe epilepsy frequency in our cohort 82.7%) agreed with the recently published TOSCA study , but was.7% agreeAMLs and renal cysts were equally observed in this population, as described previously , 24. RenThe laboratory analysis and blood pressure measurement showed absence of systematic examination. Both renal cysts and AMLs can cause hypertension and chronic kidney disease with increasing age. Annual assessment of renal function and blood pressure was already recommended in older guidelines , and proThe occurrence of astrocytic hamartomas and achromatic patches in this paediatric cohort was please merge the text here from the next row somewhat lower than the reported frequency in other cohorts including adults . Of 10 iOur study has limitations common in retrospective analyses, including incomplete data due to lack of documentation in medical records. No primary healthcare assessment was available and data collection was focused on regional hospitals and centres for habilitation thus some cases with mild disease might have been missed.This cohort study of TSC individuals from southern Sweden revealed a paradigm shift in TSC diagnosis, in that the finding of CRs on intrauterine US investigations is often the first sign of TSC, allowing early diagnosis. This allows for preventive treatment of epilepsy with vigabatrin and an early intervention with everolimus for potential mitigation of other TSC symptoms. Despite clear and updated treatment guidelines, we found that adequate follow-up is lacking in some areas, the transition from paediatric to adult care is often insufficiently prepared, and TAND data are often missing. These results confirm the previous proposal on the need for involvement of multidisciplinary teams in TSC care.


Stress-induced hyperglycaemia (SIH) is a frequent phenomenon that occurs in patients with acute ischaemic stroke. The aim of this study was to investigate the relationship between SIH and the prognosis of mechanical thrombectomy (MT) patients according to the stress hyperglycemia ratio (SHR) and glycaemic gap (GG) indicators, as well as explore its relationship with haemorrhagic transformation (HT).Patients were enrolled from January 2019 to September 2021 in our centre. SHR was calculated as fasting blood glucose divided by the A1c-derived average glucose (ADAG). GG was calculated as fasting blood glucose minus ADAG. Logistic regression was used to analyse SHR, GG with outcome and HT.P = 0.002) and GG>-0.53  were both associated with poor outcomes  at Day 90 and an increase risk of HT. Additionlly, receiver operating characteristic curves were used to assess the predictive performance of the SHR and GG on outcomes. The area under the curve for SHR to predict poor outcomes was 0.691, with an optimal cut-off value of 0.89. The area under the curve for GG was 0.682, with an optimal cut-off value of -0.53.A total of 423 patients were enrolled in the study. The incidence of SIH was as follows: 191/423 of patients with SHR > 0.89, 169/423 of patients with GG > -0.53. SHR > 0.89 (OR: 2.247, 95% CI: 1.344–3.756, High SHR and high GG are strongly associated with poor 90-day prognosis in MT patients and an increased risk of HT.The online version contains supplementary material available at 10.1186/s12883-023-03175-w. With the successive publication of several randomized controlled trials, the safety and efficacy of mechanical thrombectomy (MT) have been demonstrated, which has revolutionized the treatment of acute anterior circulation large vessel occlusive stroke , 2. DespHyperglycaemia is common in ischaemic stroke, not only in diabetic patients with high blood glucose or chronically high blood glucose levels that are undiagnosed, but also in nondiabetic patients with short-term elevated blood glucose levels due to stressful conditions, which we refer to as stress-induced hyperglycaemia (SIH) . SIH is There is no uniform definition of SIH. Some studies have defined admission glucose > 200 mg/dl (definitions vary between studies) without diabetes as SIH , 9, diabTherefore, the purpose of this study was to examine the incidence of SHR and GG in patients undergoing MT and to explore the impact of SIH assessed by SHR and GG on their outcomes.We continuously enrolled patients with anterior circulation large vessel occlusive stroke who underwent MT at the First Affiliated Hospital of Wannan Medical College from January 2019 to September 2021. The ethics of the study were reviewed and approved by the Ethics Committee of Wannan Medical College. Due to its retrospective nature, informed consent of the patients was waived. The exclusion criteria were as follows: (1) age < 18 years; (2) prestroke modified Rankin Scale (mRS) score ≥ 2; (3) CTA or DSA confirmed occlusion of the anterior cerebral artery, occlusion farther than the M2 segment of the middle cerebral artery, or multivessel occlusion; (4) absence of postoperative imaging data; (5) no postoperative laboratory indices of fasting blood glucose and glycated haemoglobin levels; and (6) no postoperative 90-day mRS score assessed by clinical follow-ups or hospital visit records, personal disease history , clinical data , and laboratory data within 24 hours . Assessments and recordings of relevant surgical data by surgical participants included symptom onset-to-puncture time (OTP), onset-to-reperfusion time (OTR), site of occluded vessel, degree of recanalization and collateral status.The condition of the collateral status was assessed according to the extent of contrast reversal within the occluded arterial basin at delayed DSA angiography, with the following parameters being defined: grade 0 was defined as little or no significant contrast reversal within the confines of the occluded vessel; grade 1 was assigned if the collateralization reached the middle cerebral artery M3 segment, and grade 2 was defined if the collaterals reached the middle cerebral artery M2 segment or the distal main stem. We defiA1c-derived average glucose(ADAG) is an indicator derived from glycated haemoglobin to assess blood glucose levels over an 8–12 week period , and it All of the patients were grouped into favourable and poor outcome groups according to the 90-day mRS scores. Normally distributed continuous variables are expressed as the mean ± standard deviation, nonnormally distributed continuous variables are expressed as quartiles and medians and categorical variables are expressed as percentages/frequencies. For comparisons between the groups (if not specified), chi-square and Fisher tests were used for the categorical variables, t tests were used for normal variables, and nonparametric tests for nonnormal variables. Variables were assessed for normality by using the Kolmogorov-Smirnov test.P < 0.05 in the univariate analysis were included in the regression models. Receiver operating characteristic (ROC) curves were used to evaluate SHR/GG to predict outcomes. Furthermore, the optimal test cut-off point was determined by calculating Youden’s index.Univariate regression analysis was used to assess the relationship between prognosis and clinical characteristics, and variables with Statistical significance was set at P < 0.05 (two-tailed). Statistical analyses were performed by using SPSS 26.0 .A total of 490 patients with LVOS who received MT were enrolled in this study, and 67 patients were excluded based on the exclusion criteria, with 423 patients ultimately meeting the study criteria.The median age of all of the examined patients was 70 years, and 250 59.1%) were male. Of all of the patients, 269 (63.6%) had a history of hypertension, 59 (13.9%) had a history of diabetes mellitus, and 221 (52.2%) had a history of atrial fibrillation. At admission, the median NIHSS and ASPECT scores were 14  and 9 , respectively. The median SHR was 0.87 , and the median GG was − 0.84 . Moreover, 191 (45.2%) of all of the patients had an SHR > 0.89, and 169 (40.0%) patients had a GG > -0.53. In the study population, 379 (89.6%) patients achieved recanalization with grade 2b/3 mTICI (Table % were maP < 0.001), and so did GG>-0.53. In addition, compared with the good prognosis group, patients in the poor prognosis group were older (P < 0.001), and had a higher proportion of male patients (P = 0.001), previous hypertensive disease (P = 0.009), embolism (P < 0.001) and ICA occlusion(P < 0.036);however, they had a lower proportion of good collateral circulation (P < 0.001) and successful reperfusion (P = 0.004), as well as, a higher median admission NIHSS (P < 0.001), a higher median baseline systolic blood pressure (P = 0.033), and a lower median admission ASPECT (P < 0.001).All of the patients in this study were divided into two groups based on 90-d mRS scores: 231(54.6%) were classified in the favourable outcome group, and the other 192 (45.4%) were classified in the poor outcome group. In the univariate analysis, the percentage of the population with SHR > 0.89 significantly differed between the favourable and poor outcome groups  and Model 2 for GG>-0.53  demonstrated reduced 90-day good functional outcomes (Table 3), respectively. In addition, in Model 1, male , high baseline NIHSS , low baseline ASPECT , and poor collateral score  were independently associated with poor functional outcomes at 90 days, and in Model 2, male , high baseline NIHSS , low baseline ASPECT , and poor collateral circulation were similar.In both regression models, after adjusting for variables with Receiver operating characteristic (ROC) curve analysis was used to determine the functional outcomes of SHR and GG for LVOS patients who received MT. The optimal cut-off points for SHR and GG to predict prognostic outcome after MT in LVOS patients were 0.89(sensitivity of 0.635 and specificity of 0.701) and − 0.53(sensitivity of 0.573 and specificity of 0.749) respectively. Moreover, the area under the curve (AUC) for the ability of SHR and GG levels to predict poor outcomes was 0.691 and 0.682, respectively , IT (P = 0.003), OTP (P = 0.001), OTR (P < 0.001), SHR > 0.89 (P < 0.001) and GG>-0.53 (P = 0.001) differed between the two groups  and subsequently included surgical data ; in addition, pharmacological treatment was included . After adjusting for the inclusion of different variables, all of the results showed that SHR > 0.89 and GG>-0.53 increased the risk of HT. In addition, IT, antiplatelet history and low ASPECT increased the risk of HT .All of the patients were divided into two groups according to HT, of which 111(26.2%) patients experienced HT. In the univariate analysis, we found that antiplatelet/anticoagulant history  or 40.2% (GG), which was much higher than the proportion of patients with diabetes and also higher than the proportion of patients with SIH as defined by previous studies. In our study, we found that high SHR and high GG independently predicted the outcome after MT. Second, SHR and GG increased the risk of HT in patients who underwent MT.There have been a number of studies on SIH, but the definition of SIH has been shown to vary. In recent years, some studies have used an increase in absolute blood glucose (fasting blood glucose or random blood glucose levels) to indicate the occurrence of SIH, 16. TheThe detailed mechanism of the SHR and prognosis of MT patients is not clear, however, some viewpoints have been accepted by most scholars. SIH involves an elevation of blood glucose secondary to major illnesses such as trauma, stroke or even surgery. SIH is IR is a common phenomenon of elevated blood glucose in stroke patients. InsulinP = 0.004). Moreover, the small sample size of reperfusion failure resulted in its nonsignificance in the multiple regression analysis.It is noteworthy that complete recanalization was a factor that improved prognosis in previous studies; however, mTICI had no statistical significance in our multifactorial analysis, but was significant in the univariate analysis. We may be able to explain this conclusion from a statistical point of view. The reperfusion success rate of the 5 major randomized trials was approximately 70%, whereasIt is worth noting that the present study had some limitations. First, our study was a single-centre retrospective study that requires a larger sample size and prospective studies for support. Second, due to the small sample size of diabetic patients in this study, we failed to analyse in different background glucose groups. In addition, although we did not perform glycaemic interventions prior to FBG collection whenever possible, we intervened in a very small number of patients by using subcutaneous insulin injection in consideration of their condition, however we did not exclude these patients from the study. Finally, we were unable to collect blood glucose related metrics over multiple time periods, and a subcutaneous implantable blood glucose monitoring device may be a good option.This study showed that both SIH markers(SHR and GG) were significantly associated with poor outcomes in MT patients and increased risk of HT.Below is the link to the electronic supplementary material.Supplementary Material 1Supplementary Material 2Supplementary Material 3