Morbidity and mortality from tuberculosis (TB) are high in Taiwan. We conducted a nationwide population‐based matched cohort study using data retrieved from the Taiwan's National Health Insurance ...Research Database to determine the impact of TB after liver transplantation (LT). During 2000–2011, we identified 3202 liver transplant recipients and selected subjects from the general population matched for age, sex, and comorbidities on the same index date of recognition of LT with a 1:10 ratio. The data were analyzed using Cox proportional hazards models. Compared to the matched cohort, liver transplant patients had a higher risk for TB (adjusted HR 2.25, 95% CI 1.65–3.05, p < 0.001), and those with TB showed higher mortality (HR 2.27, 95% CI 1.30–3.97, p = 0.004). Old age (HR 2.64, 95% CI 1.25–5.54, p = 0.011) and mammalian target of rapamycin inhibitors (mTORis) (HR 3.09, 95% CI 1.68–5.69, p < 0.001) were significant risk factors for TB in LT; mTORis were also associated with mortality after adjusting for confounders (HR 2.13, 95% CI 1.73–2.62, p < 0.001). Therefore, regular surveillance of TB and treatment of latent TB infection in high‐risk patients after LT are important, especially in TB‐endemic areas.
The authors demonstrate the high risk of tuberculosis in liver transplant recipients and define old age and mammalian target of rapamycin inhibitors as risk factors for tuberculosis after liver transplantation, which provides a practical guide to selecting high‐risk liver transplant patients for regular surveillance and treatment of tuberculosis.
Renin–angiotensin–aldosterone system inhibitors (RAASi) are associated with improved survival outcomes in patients receiving immune checkpoint inhibitors (ICIs), but the data on the response to ...treatment and tumour-based endpoints across different tumour types are unknown.
We carried out a retrospective study at two tertiary referral centres in Taiwan. All adult patients treated with ICIs between January 2015 and December 2021 were included. The primary outcome was overall survival and the secondary outcomes were progression-free survival (PFS) and clinical benefit rates.
In total, 734 patients were enrolled in our study, of which 171 were RAASi users and 563 were non-users. Compared with non-users, RAASi users had a longer median overall survival 26.8 (interquartile range 11.3–not reached) versus 15.2 (interquartile range 5.1–58.4) months, P < 0.001 and PFS 12.2 (interquartile range 3.9–34.5) versus 5.0 (interquartile range 2.2–15.2) months, P < 0.001. In univariate Cox proportional hazard analyses, the use of RAASi was associated with a 40% reduction in the risk of mortality hazard ratio 0.58 (95% confidence interval 0.44–0.76), P < 0.001 and disease progression hazard ratio 0.62 (95% confidence interval 0.50–0.77), P < 0.001. The association remained significant after adjusting for underlying comorbidities and cancer therapy in multivariate Cox analyses. A similar trend was observed for PFS. Furthermore, RAASi users experienced a greater clinical benefit rate than non-users (69% versus 57%, P = 0.006). Importantly, the use of RAASi before ICI initiation was not associated with improved overall survival and PFS. RAASi were not associated with an increased risk of adverse events.
The use of RAASi is associated with improved survival outcomes, treatment response and tumour-based endpoints in patients undergoing immunotherapy.
•RAASi were associated with improved clinical outcomes across a broad range of cancer patients receiving ICI.•Subgroup analysis showed that ARB were associated with improved clinical outcomes in patients undergoing immunotherapy.•The use of RAASi before immune checkpoint blockade was not associated with improved survival.•RAASi were not associated with increased risk of adverse events among cancer patients receiving ICI.
The relationship between tuberculosis (TB) and subsequent chronic kidney disease (CKD) remains unclear. Therefore, we examined the risk of CKD among patients with TB in a nationwide study.
We ...conducted a retrospective cohort study using data from the National Health Insurance system of Taiwan. The cohort included 8735 patients who were newly diagnosed with TB. Patients were recruited between 1998 and 2002, and the date of diagnosis was defined as the index date. Each patient was randomly matched with four people from the general population without TB, according to age, gender and the index year. The occurrence of CKD was followed up until the end of 2011. The relative risks of CKD were estimated using the Cox proportional hazard model after adjusting for age, gender, index year and comorbidities.
The overall incidence of CKD was 1.27-fold greater in the TB cohort than in the non-TB cohort. The adjusted hazard ratio (HR) of CKD associated with TB was higher in women (1.72; 95% confidence interval CI: 1.33-2.22), those aged <50 years (1.67; 95% CI: 1.15-2.41) and those without comorbidities (1.39; 95% CI: 1.06-1.83). In addition, patients with more comorbidities among hypertension, diabetes and hyperlipidemia have a greater risk of developing CKD in both cohorts, and the adjusted HRs were higher in the TB cohort than in the non-TB cohort.
TB patients had a significantly higher risk of developing CKD than the general population. The detailed mechanisms need further investigation.
Summary
Background
The Milan criteria are used to select candidates with small hepatocellular carcinoma (HCC) for liver transplantation. Due to severe shortage of donors, majority of patients within ...the Milan criteria need to seek alternative treatments.
Aim
To propose a prognostic model for these patients undergoing non‐transplant therapies.
Methods
A total of 1106 HCC patients, who were within the Milan criteria and received non‐transplant therapies were retrospectively analysed. Patients were randomly assigned to the derivation and validation set according to treatments. A prognostic model was constructed from independent predictors of survival identified in the multivariate Cox model of the derivation set and was confirmed in the validation set.
Results
In the Cox model, serum bilirubin ≥1.5 mg/dL risk ratio (RR): 1.525, P = 0.016, α‐fetoprotein (AFP) ≥100 ng/mL (RR: 1.728, P < 0.001), mild ascites (RR: 1.705, P = 0.025) and moderate/severe ascites (RR: 4.163, P < 0.001) were independent predictors of poor survival in the derivation set (n = 553). A prognostic model with a total of 0–4 points was derived with the sum of three variables: 1 point each for bilirubin ≥1.5 mg/dL, AFP ≥100 ng/mL and mild ascites, and 2 points for moderate/severe ascites. This scoring system accurately predicted the survival in the validation set (n = 553; P < 0.001). The model consistently discriminated the survival in patients stratified by curative and noncurative treatments (both P values <0.001).
Conclusion
The newly proposed prognostic scoring model, based on serum bilirubin and AFP level, and severity of ascites, is informative to predict the survival in non‐transplant HCC patients within the Milan criteria.
Localized chromatin modifications of histone tails play an important role in regulating gene transcription, and aberration of these processes leads to carcinogenesis. Methylated histone lysine ...residues, a key player in chromatin remodeling, are demethylated by the JmjC class of enzymes. Here we show that JMJD5 (now renamed KDM8), a JmjC family member, demethylates H3K36me2 and is required for cell cycle progression. Chromatin immunoprecipitation assays applied to human genome tiling arrays in conjunction with RNA microarray revealed that KDM8 occupies the coding region of cyclin A1 and directly regulates transcription. Mechanistic analyses showed that KDM8 functioned as a transcriptional activator by inhibiting HDAC recruitment via demethylation of H3K36me2, an epigenetic repressive mark. Tumor array experiments revealed KDM8 is overexpressed in several types of cancer. In addition, loss-of-function studies in MCF7 cells leads to cell cycle arrest. These studies identified KDM8 as an important cell cycle regulator.
Defects in the biogenesis of or transport through primary cilia affect Hedgehog protein signaling, and many Hedgehog pathway components traffic through or accumulate in cilia. The Hedgehog receptor ...Patched negatively regulates the activity and ciliary accumulation of Smoothened, a seven-transmembrane protein that is essential for transducing the Hedgehog signal. We found that this negative regulation of Smoothened required the ciliary localization of Patched, as specified either by its own cytoplasmic tail or by provision of heterologous ciliary localization signals. Surprisingly, given that Hedgehog binding promotes the exit of Patched from the cilium, we observed that an altered form of Patched that is retained in the cilium nevertheless responded to Hedgehog, resulting in Smoothened activation. Our results indicate that whereas ciliary localization of Patched is essential for suppression of Smoothened activation, the primary event enabling Smoothened activation is binding of Hedgehog to Patched, and Patched ciliary removal is secondary.
The Drosophila Hedgehog receptor functions to regulate the essential downstream pathway component, Smoothened, and to limit the range of signaling by sequestering Hedgehog protein signal within ...imaginal disc epithelium. Hedgehog receptor function requires both Patched and Ihog activity, the latter interchangeably encoded by interference hedgehog (ihog) or brother of ihog (boi). Here we show that Patched and Ihog activity are mutually required for receptor endocytosis and degradation, triggered by Hedgehog protein binding, and causing reduced levels of Ihog/Boi proteins in a stripe of cells at the anterior/posterior compartment boundary of the wing imaginal disc. This Ihog spatial discontinuity may contribute to classically defined cell segregation and lineage restriction at the anterior/posterior wing disc compartment boundary, as suggested by our observations that Ihog activity mediates aggregation of otherwise non-adherent cultured cells and that loss of Ihog activity disrupts wing disc cell segregation, even with downstream genetic rescue of Hedgehog signal response.
The increased health risks associated with obesity have been found to occur in Asians at lower body mass indices (BMIs). To determine the optimal cut-off values for overweight or obesity in Taiwan, ...we examined the relationships between four anthropometric indices and cardiovascular risk factors.
The data were collected from four health-screening centers from 1998 to 2000 in Taiwan. Included were 55 563 subjects (26 359 men and 29 204 women, mean age=37.3+/-10.9 and 37.0+/-11.1 y, respectively). None had known major systemic diseases or were taking medication. Individual body weight, height, waist circumference (WC), and a series of tests related to cardiovascular risk (blood pressure, fasting plasma glucose, triglycerides, total cholesterol, low- and high-density lipoprotein cholesterol) were assessed and their relationships were examined. Receiver operating characteristic (ROC) analysis was used to find out the optimal cut-off values of various anthropometric indices to predict hypertension, diabetes mellitus and dyslipidemia.
Of the four anthropometric indices we studied, waist-to-height ratio (WHtR) in women was found to have the largest areas under the ROC curve (women=0.755, 95% CI 0.748-0.763) relative to at least one risk factor (ie hypertension or diabetes or dyslipidemia). The optimal cut-off values for overweight or obesity from our study in men and women showed that BMIs of 23.6 and 22.1 kg/m(2), WCs of 80.5 and 71.5 cm, waist-to-hip ratios (WHpR) of 0.85 and 0.76, and WHtR of 0.48 and 0.45, respectively, may be more appropriate in Taiwan.
WHtR may be a better indicator for screening overweight- or obesity-related CVD risk factors than the other three indexes (BMI, WC and WHpR) in Taiwan. Our study also supported the hypothesis that the cut-off values using BMI and WC to define obesity should be much lower in Taiwan than in Western countries.
Abstract
Recent studies raised concerns about the increasing use of gabapentinoids in different countries. With their potential for misuse and addiction, understanding the global consumption of ...gabapentinoids will offer us a platform to examine the need for any interventional policies. This longitudinal trend study utilised pharmaceutical sales data from 65 countries and regions across the world to evaluate the global trends in gabapentinoid consumption between 2008-2018. The multinational average annual percentage change of gabapentinoid consumption was +17.20%, increased from 4.17 defined daily dose per ten thousand inhabitants per day (DDD/TID) in 2008 to 18.26 DDD/TID in 2018. High-income countries had the highest pooled gabapentinoid consumption rate (39.92 DDD/TID) in 2018, which was more than six times higher than the lower-middle income countries (6.11 DDD/TID). The study shows that despite differences in healthcare system and culture, a consistent increase in gabapentinoid consumption is observed worldwide, with high-income countries remaining the largest consumers.
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