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Background Data are limited regarding the risk of hepatitis C virus (HCV) reinfection after treatment-induced sustained virologic response (SVR) in patients on haemodialysis. Aims To assess the risk of HCV reinfection among patients on haemodialysis with treatment-induced SVR. Methods Patients on haemodialysis patients who achieved SVR12 with interferon (IFN) or direct-acting antiviral (DAA)-based treatment received follow-up at SVR24 and then biannually with HCV RNA measurements. HCV reinfection was defined as the resurgence of viremia by different viral strains beyond SVR12 . The low-risk general population who achieved SVR12 and who underwent the same post-SVR12 surveillance served as the reference group. Crude reinfection rates per 100 person-years (PYs) were calculated. Multivariate Cox regression analysis was performed to estimate the relative risk of HCV reinfection between the two groups. Results We recruited 374 patients on haemodialysis and 1571 reference patients with a mean post-SVR12 follow-up of 4.7 and 6.1 years. All haemodialysis patients who achieved SVR12 also achieved SVR24 . The incidence rates of HCV reinfection were 0.23 per 100 PYs (95% confidence interval [CI]: 0.09-0.59) in haemodialysis patients and 0.16 per 100 PYs (95% CI: 0.10-0.26) in the reference group. The risk of HCV reinfection in patients on haemodialysis was comparable to that in the reference patients (hazard ratio [HR]: 1.39; 95% CI: 0.44-4.38, P = 0.57). Conclusions The risk of HCV reinfection in patients on haemodialysis who achieve SVR12 is low and comparable to that in the low-risk general population. HCV microelimination in this special population is feasible once universal screening and scaled-up treatment are implemented.

Increasing evidence supports the role of the immune microenvironment and associated signalling in the pathogenesis of myelodysplastic syndromes (MDS). Nevertheless, the clinical relevancy of immune signals in patients with MDS remains elusive. To address this, we used single-sample gene-set enrichment analysis to score immune signatures of bone marrow (BM) samples from 176 patients with primary MDS. Enhanced signatures of 'immature dendritic cells' and 'natural killer cells with cluster of differentiation (CD)56bright' were correlated with better overall survival (OS), whilst higher 'CD103+ signature' was associated with reduced survival. An MDS-Immune-Risk (MIR) scoring system was constructed based on the weighted sums derived from Cox regression analysis. High MIR scores were correlated with higher revised International Prognostic Scoring System (IPSS-R) scores and mutations in ASXL transcriptional regulator 1 (ASXL1), Runt-related transcription factor 1 (RUNX1), and tumour protein p53 (TP53). High-score patients had significantly inferior leukaemia-free survival (LFS) and OS than low-score patients. The prognostic significance of MIR scores for survival remained valid across IPSS-R subgroups and was validated in two independent cohorts. Multivariable analysis revealed that a higher MIR score was an independent adverse risk factor for LFS and OS. We further proposed a model with the combination of MIR score and gene mutations to be complementary to IPSS-R for the prognostication of LFS and OS of patients with MDS.

Myeloproliferative neoplasms (MPNs) are characterized by upregulation of proinflammatory cytokines and immune dysregulation, which provide a reasonable basis for immunotherapy in patients. Megakaryocytes are crucial in the pathogenesis of primary myelofibrosis (PMF), the most clinically aggressive subtype of MPN. In this study, we aimed to explore PD‐L1 (programmed death‐ligand 1) expression in megakaryocytes and its clinical implications in PMF. We analyzed PD‐L1 expression on megakaryocytes in PMF patients by immunohistochemistry and correlated the results with clinicopathological features and molecular aberrations. We employed a two‐tier grading system considering both the proportion of cells positively stained and the intensity of staining. Among the 85 PMF patients, 41 (48%) showed positive PD‐L1 expression on megakaryocytes with the immune‐reactive score ranging from 1 to 12. PD‐L1 expression correlated closely with higher white blood cell count (p = 0.045), overt myelofibrosis (p = 0.010), JAK2V617F mutation (p = 0.011), and high‐molecular risk mutations (p = 0.045), leading to less favorable overall survival in these patients (hazard ratio 0.341, 95% CI 0.135–0.863, p = 0.023). Our study provides unique insights into the interaction between immunologic and molecular phenotypes in PMF patients. Future work to explore the translational potential of PD‐L1 in the clinical setting is needed.

Lactobacillus plantarum PS128 has been reported as a psychobiotic to improve mental health through the gut–brain axis in experimental animal models. To explore its mechanism of action in the gut, this study aimed to analyze the effects of L. plantarum PS128 ingestion on naïve and loperamide (Lop)-induced constipation mice. We found that, in the two mouse models, the weight, number, and water content of feces in the L. plantarum PS128 group were higher than those in the vehicle control group. Histological observation revealed that L. plantarum PS128 increased the level of colonic mucins including the major mucin MUC2. In addition, the charcoal meal test showed that L. plantarum PS128 significantly increased the small intestine transit in naïve mice, but not in the Lop-treated mice. Since intestinal serotonin has been found to modulate motility, we further analyzed the expression of genes related to serotonin signal transduction in the small intestine of naïve mice. The results showed that L. plantarum PS128 significantly altered the expression levels of Tph1, Chga, Slc6a4, and Htr4, but did not affect the expression levels of Tph2, Htr3a, and Maoa. Furthermore, immunohistochemistry revealed that L. plantarum PS128 significantly increased the number of serotonin-containing intestinal cells in mice. Taken together, our results suggest that L. plantarum PS128 could promote intestinal motility, mucin production, and serotonin signal transduction, leading to a laxative effect in mice.

Next-generation sequencing (NGS) has been applied to measurable/minimal residual disease (MRD) monitoring after induction chemotherapy in patients with acute myeloid leukemia (AML), but the optimal time point for the test remains unclear. In this study, we aimed to investigate the clinical significance of NGS MRD at 2 different time points. We performed targeted NGS of 54 genes in bone marrow cells serially obtained at diagnosis, first complete remission (first time point), and after the first consolidation chemotherapy (second time point) from 335 de novo AML patients. Excluding DNMT3A, TET2, and ASXL1 mutations, which are commonly present in individuals with clonal hematopoiesis of indeterminate potential, MRD could be detected in 46.4% of patients at the first time point (MRD1st), and 28.9% at the second time point (MRD2nd). The patients with detectable NGS MRD at either time point had a significantly higher cumulative incidence of relapse and shorter relapse-free survival and overall survival. In multivariate analysis, MRD1st and MRD2nd were both independent poor prognostic factors. However, the patients with positive MRD1st but negative MRD2nd had a similar good prognosis as those with negative MRD at both time points. The incorporation of multiparameter flow cytometry and NGS MRD revealed that the presence of NGS MRD predicted poorer prognosis among the patients without detectable MRD by multiparameter flow cytometry at the second time point but not the first time point. In conclusion, the presence of NGS MRD, especially after the first consolidation therapy, can help predict the clinical outcome of AML patients.

Objectives Albuminuria and serum adiponectin levels are factors that have been associated with the development of cardiovascular disease in patients with diabetes mellitus. Here we investigated the relationship between serum adiponectin levels and aortic stiffness in nondialysis diabetic kidney disease patients with stage 3–5 chronic kidney disease. Methods Fasting blood samples were obtained from 80 nondialysis diabetic kidney disease patients with stage 3–5 chronic kidney disease. Carotid-femoral pulse wave velocity (cfPWV) was measured using applanation tonometry; cfPWV values of >10 m/s were defined as aortic stiffness. Serum adiponectin levels were determined by enzyme immunoassay. Results Forty-two patients (52.5%) with nondialysis diabetic kidney disease were diagnosed with aortic stiffness. The patients in this group were older ( p = 0.011), had higher systolic blood pressure ( p = 0.002) and urine albumin-to-creatinine ratios ( p = 0.013), included fewer females ( p = 0.024), and had lower serum adiponectin ( p = 0.001) levels than those in the control group. Multivariable logistic regression analysis revealed that serum adiponectin was independently associated with aortic stiffness (odds ratio = 0.930, 95% confidence interval: 0.884–0.978, p = 0.005) and also positively correlated with cfPWV values by multivariable linear regression ( β = –0.309, p = 0.002) in nondialysis diabetic kidney disease patients. Conclusions The results suggested that serum adiponectin levels could be used to predict aortic stiffness in nondialysis diabetic kidney disease patients with stage 3–5 chronic kidney disease.

Background Hyperbilirubinemia is a predictor of severe drug-induced liver injury (DILI). Hepatobiliary ATP-binding cassette (ABC) transporters play an important role in the transportation of many drugs and bilirubin; however, little is known about these transporters and the risk of DILI. The aim of this study was to explore associations between genetic variations in important ABC transporters and susceptibility to DILI, with a particular focus on hyperbilirubinemia. Methods A total of 200 patients with DILI and 200 healthy controls were enrolled as the training dataset. Another 106 patients with DILI were recruited as the validation dataset. They were genotyped for ABCB11 (BSEP) rs2287622, ABCB1 (MDR1) rs1128503, rs1045642, ABCB4 (MDR3) rs2230028, ABCC2 (MRP2) rs1885301, rs717620, rs2273697, rs3740066 and rs8187710 using polymerase chain reaction-based TaqMan genotyping assays. Results There were no statistical differences in any of the nine ABC transporter single nucleotide polymorphisms between the DILI and control groups. However, in the DILI group, the patients with hyperbilirubinemia had a higher frequency of the ABCC2 rs717620 C/T and T/T genotypes than those without hyperbilirubinemia (44.2% vs 20.2%, p = 0.001). After adjusting for other confounding factors, the ABCC2 rs717620 T variant was still associated with an increased risk of hyperbilirubinemia (adjusted odds ratio [OR]: 3.83, 95% confidence interval [CI]: 1.73-8.48, p = 0.001). This association was confirmed by the validation dataset (adjusted OR: 3.92, 95% CI: 1.42-10.81, p = 0.015). We also found that the mortality group had higher frequencies of the ABCC2 (MRP2) rs717620 C/T and T/T genotypes than the survival group (50.0% vs 27.9%, p = 0.048). Conclusion Carriage of the ABCC2 (MRP2) rs717620 T variant may increase the risk of hyperbilirubinemia and mortality in patients with DILI. Screening for this variant may help to prevent and mitigate drug-induced hyperbilirubinemia.

INTRODUCTION: Nontraumatic acute abdomen (NTAA) in dialysis patients is a challenging issue. The aetiologies of NTAA vary considerably depending on the renal replacement therapy (RRT) modality. Although haematological parameters and contributing factors have been reported to be associated with outcomes for dialysis patients, their clinical effect on the length of hospital stay (LOS) remains unknown. METHODS: We retrospectively analysed 52 dialysis patients (peritoneal dialysis [PD], n = 33; haemodialysis [HD], n = 19) and 30 non-dialysis patients (as controls) between January 2011 and December 2014. To attenuate the selection bias, non-dialysis patients with NTAA were matched to cases at a ratio of 1:1 by age, gender and comorbidities (diabetes mellitus and hypertension). Their demographic characteristics, laboratory data, clinical assessment scores and LOS were analysed. RESULTS: The PD group exhibited a significantly higher neutrophil percentage, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR); longer LOS; and lower lymphocyte percentage and absolute lymphocyte count than the control group. After multivariate analysis adjustment, female gender, longer RRT duration and higher intact parathyroid hormone (iPTH) levels were associated with a lower probability of being discharged home. In the dialysis group, a higher iPTH level (> 313 μg/mL) was positively correlated with longer LOS. iPTH level combined with NLR can be used as a surrogate marker for predicting longer LOS (p < 0.001). CONCLUSION: NTAA dialysis patients with female gender, longer RRT duration and higher iPTH levels are prone to experiencing longer LOS. In addition, the combination of iPTH and NLR is a significant determinant for LOS in NTAA dialysis patients.

Background Malignant pleural effusion (MPE)-macrophage (Mφ) of lung cancer patients within unique M1/M2 spectrum showed plasticity in M1–M2 transition. The M1/M2 features of MPE-Mφ and their significance to patient outcomes need to be clarified; furthermore, whether M1-repolarization could benefit treatment remains unclear. Methods Total 147 stage-IV lung adenocarcinoma patients undergoing MPE drainage were enrolled for profiling and validation of their M1/M2 spectrum. In addition, the MPE-Mφ signature on overall patient survival was analyzed. The impact of the M1-polarization strategy of patient-derived MPE-Mφ on anti-cancer activity was examined. Results We found that MPE-Mφ expressed both traditional M1 (HLA-DRA) and M2 (CD163) markers and showed a wide range of M1/M2 spectrum. Most of the MPE-Mφ displayed diverse PD-L1 expression patterns, while the low PD-L1 expression group was correlated with higher levels of IL-10. Among these markers, we identified a novel two-gene MPE-Mφ signature, IL-1β and TGF-β1, representing the M1/M2 tendency, which showed a strong predictive power in patient outcomes in our MPE-Mφ patient cohort (N = 60, p = 0.013) and The Cancer Genome Atlas Lung Adenocarcinoma dataset (N = 478, p Conclusions We identified MPE-Mφ on the M1/M2 spectrum and plasticity and described a two-gene M1/M2 signature that could predict the outcome of late-stage lung cancer patients. In addition, we found that “re-education” of these MPE-Mφ toward anti-cancer M1 macrophages using clinically applicable strategies may overcome tumor immune escape and benefit anti-cancer therapies.

Background Nonalcoholic steatohepatitis (NASH) is closely related to reactive oxygen species (ROS). Superoxide anion radicals, the main product of ROS, can be reduced by manganese superoxide dismutase (SOD2) to hydrogen peroxide, which is further reduced by catalase (CAT) and glutathione peroxidase (GPX) to water. We aimed to investigate the association between the most important genetic variants of SOD2, CAT, and GPX1 and susceptibility to NASH. Methods A total of 126 adults with liver tissue-verified NASH, 56 patients with liver tissue-verified nonalcoholic fatty liver (NAFL), and 153 healthy controls were enrolled. Their DNA profiles were retrieved for genotype assessment of SOD2 47T>C (rs4880), CAT -262C>T (rs1001179), and GPX1 593C>T (rs1050450) variation. Results There were statistical differences between the SOD2 and CAT genotypes across the NASH, NAFL, and control groups, but not GPX1. The NASH group had a significantly higher frequency of subjects with SOD2 C allele (38.8%) compared with the NASL group (25.0%) and the controls (22.9%, p = 0.010). Similarly, the NASH group had a significantly higher percentage of subjects with CAT T allele (23.0%) compared with the NAFL group (10.7%) and the controls (7.2%, p = 0.001). For subjects with both the SOD2 C allele and CAT T allele, 88.2% were in the NASH group. After adjusting for confounders, the CAT mutant T allele and SOD2 mutant C allele were still the highest independent risk factors for NASH (odds ratio [OR] 3.10 and 2.36, respectively). In addition, there was a synergistic effect for those two alleles and the occurrence of NASH with an adjusted OR of 8.57 (p = 0.030). Conclusion The genetic variations of CAT and SOD2 may increase the risk of NASH, which may aid in the screening of patients who are at high risk of NASH, and offer a potential anti-oxidant targeting route for the treatment of NASH.

The major aim of the present study was to determine the effects of quercetin, a well-known flavonoid, on attenuating cisplatin (CDDP)-induced fat loss and the possible mechanisms. Tumor-bearing nude mice and tumor-free BALB/c mice were administrated with CDDP alone or in combination with quercetin by a diet containing 0.1% or 1% quercetin (LQ or HQ) or by intraperitoneal injection (IQ) to determine the effects of quercetin on the anticancer effect of CDDP or CDDP-induced fat loss. The effects of quercetin on fat accumulation in CDDP-exposed 3T3-L1 cells were also determined. We first showed that HQ and IQ significantly enhanced the anticancer effect of CDDP by upregulating p53- and p21-associated pathways, while tended to attenuate CDDP-induced fat loss in tumor-bearing nude mice. The study in 3T3-L1 cells showed that CDDP decreased the fat accumulation accompanied by strong upregulation of the expression of six genes which are associated with fat metabolism, while quercetin completely suppressed such an effect. The tumor-free BALB/c mice study consistently showed a protective effect of HQ on CDDP-induced body weight and epididymal fat loss. HQ also increased the fat levels in liver and muscle tissues. In epididymal fat tissues, HQ consistently attenuated CDDP-induced changes in fat metabolism-associated gene expression. However, CDDP alone or in combination with HQ did not affect the food intake. This study demonstrates that quercetin possesses the potential to suppress CDDP-induced fat loss may partly through the regulation of the fat metabolism-associated gene expression.

Objectives Herpes zoster and postherpetic neuralgia (PHN) are often refractory to current standard treatments and can reduce patients' quality of life (QoL). Pulsed radiofrequency (PRF) effectively controls intractable neurological pain. The aim of the study was to conduct a systematic review and meta-analysis to evaluate the efficacy of PRF in PHN management. Materials and methods We searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs) published up to October 2019. The primary outcomes were pain levels and rescue analgesia at different postintervention time intervals. The secondary outcomes were QoL and sleep quality. Results We reviewed 6 RCTs involving 420 patients. The meta-analysis revealed that the PRF group exhibited significantly lower pain scores in PHN than did the control group at 2 to 3 days (weighted mean differences [WMD]=-2.82; 95% confidence interval [CI]: -5.08 to -0.55), 1 week (WMD=-2.95; 95% CI: -4.53 to -1.37), 2 weeks (WMD=-3.17; 95% CI: -4.11 to -2.23), 4 weeks (WMD=-2.59; 95% CI: -3.40 to -1.79), 8 weeks (WMD=-3.02; 95% CI: -4.17 to -1.88), and 6 months (WMD=-1.94; 95% CI: -2.85 to -1.03). After intervention, QoL was significantly higher in the PRF group than in the control group. No major complications were reported. Discussion PRF safely and effectively reduced pain scores and improved QoL in patients with herpes zoster in the cervical to lumbosacral areas. PRF could be considered during refractory PHN treatment. Future studies require standardized PRF settings and outcome assessment tools, including physical and emotional function assessments.

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.

Background: Hyperphosphatemia in end-stage renal disease patients is prevalent and associated with increasing cardiac mortality. Restricting dietary phosphate intake is a key element in controlling hyperphosphatemia, but most patients fail due to lack of knowledge and sustainability. In this study, we aimed to examine whether incorporating a smartphone application (APP) into a multidisciplinary caring system can decrease the prevalence of hyperphosphatemia in hemodialysis patients. Methods: We designed a quasi-experimental study to enroll patients undergoing regular hemodialysis and assigned them to receive APP-assisted caring program (ACP group, n = 30) or standard education caring program (SCP group, n = 30). Both caring programs targeting dietary phosphate control were administered. Patients’ general characteristics, self-care efficacy scales, knowledge test of phosphate control, and results of monthly blood biochemistry were analyzed. Findings: Knowledge of diet phosphate control and self-care efficacy were significantly higher in the ACP group. Notably, the knowledge improvement was higher in patients aged over 60 years. Compared to the SCP group, the percentage of patients with successful hyperphosphatemia control was significantly higher in the ACP group ( p = 0.0398). Conclusion: The APP-assisted caring program benefits patients with regular hemodialysis to achieve better dietary phosphate control without compromising proper protein intake.

BACKGROUND The mainstay therapy for latent tuberculosis infection is a 9-month regimen of daily isoniazid (9H) and a 3-month regimen of 12 once-weekly doses of isoniazid and rifapentine (3HP). We performed this updated meta-analysis to compare hepatotoxicity, efficacy and completion rate between these two regimens. METHODS We searched all literature in the major medical databases using the subject search terms "isoniazid" and "rifapentine", and performed a systemic review and meta-analysis. RESULTS A total of 14 studies were eligible for the meta-analysis, which included 5600 (49%) patients who received the 3HP regimen and 5919 (51%) patients who received the 9H regimen. A total of 202 (2%) patients had a drug-induced liver injury (DILI) and 11 317 (98%) did not. The pooled odds ratio (OR) of DILI in the 3HP regimen was 0.18 (95% confidence interval [CI], 0.12-0.26; p < 0.0001), compared with the 9H regimen. This result remained consistent in subgroup analyses of ethnicity and study design. The 3HP regimen was superior to the 9H regimen in the prevention of active tuberculosis (OR, 0.38, 95% CI, 0.18-0.80, p = 0.01). Furthermore, the 3HP regimen was associated with a better completion rate than the 9H regimen (OR: 2.30, 95% CI, 2.10-2.53, p < 0.0001). CONCLUSION The 3HP regimen is superior to the 9H regimen, with less hepatotoxicity, and better efficacy and completion rate in treating latent tuberculosis infection.

Muscle wasting and hyperphosphatemia are becoming increasingly prevalent in patients who exhibit a progressive decline in kidney function. However, the association between serum phosphate (Pi) level and sarcopenia in advanced chronic kidney disease (CKD) patients remains unclear. We compared the serum Pi levels between advanced CKD patients with (n = 51) and those without sarcopenia indicators (n = 83). Low appendicular skeletal muscle mass index (ASMI), low handgrip strength, and low gait speed were defined per the standards of the Asian Working Group for Sarcopenia. Mean serum Pi level was significantly higher in advanced CKD patients with sarcopenia indicators than those without sarcopenia indicators (3.88 ± 0.86 vs. 3.54 ± 0.73 mg/dL, p = 0.016). Univariate analysis indicated that serum Pi was negatively correlated with ASMI, handgrip strength, and gait speed. Multivariable analysis revealed that serum Pi was significantly associated with handgrip strength (standardized β = −0.168, p = 0.022) and this association persisted even after adjustments for potential confounders. The optimal serum Pi cutoff for predicting low handgrip strength was 3.65 mg/dL, with a sensitivity of 82.1% and specificity of 56.6%. In summary, low handgrip strength is common in advanced CKD patients and serum Pi level is negatively associated with handgrip strength.

Heavy metals causing chronic nephrotoxicity may play a key role in the pathogenesis of chronic kidney disease (CKD). This study hypothesized that plasma folate and vitamin B12 would modify the association of CKD with total urinary arsenic and blood lead and cadmium levels. We recruited 220 patients with CKD who had an estimated glomerular filtration rate of &lt, 60 mL/min/1.73 m2 for ≥3 consecutive months and 438 sex- and age-matched controls. We performed inductively coupled plasma mass spectrometry to measure blood cadmium and lead levels. The urinary arsenic level was determined using a high-performance liquid chromatography–hydride generator–atomic absorption spectrometry. Plasma vitamin B12 and folate levels were measured through the SimulTRAC-SNB radioassay. Compared with patients with plasma vitamin B12 ≤ 6.27 pg/mL, the odds ratio (OR) and 95% confidence interval of CKD for patients with plasma vitamin B12 &gt, 9.54 pg/mL was 2.02 (1.15–3.55). However, no association was observed between plasma folate concentration and CKD. A high level of plasma vitamin B12 combined with high levels of blood lead and cadmium level and total urinary arsenic tended to increase the OR of CKD in a dose-response manner, but the interactions were nonsignificant. This is the first study to demonstrate that patients with high plasma vitamin B12 level exhibit increased OR of CKD related to high levels of blood cadmium and lead and total urinary arsenic.

(1) Background: Diabetic retinopathy (DR) can cause blindness. Current guidelines on diabetic eye care recommend more frequent eye examinations for more severe DR to prevent deterioration. However, close follow-up and early intervention at earlier stages are important for the prevention of disease progression of other diabetes mellitus (DM) complications. The study was designed to investigate the association between different stages of DR in type 2 DM patients and the progression of DR, (2) Methods: A total of 2623 type 2 DM patients were included in this study. In these patients, a total of 14,409 fundus color photographs was obtained. The primary outcome was the progression of DR, (3) Results: The progression of DR was highly associated with the initial grade of DR (p &lt, 0.001). Severe nonproliferative diabetic retinopathy (NPDR) was the most likely to progress to proliferative diabetic retinopathy (PDR), followed by moderate NPDR, mild NPDR, and no retinopathy. However, progression to the next stage of DR showed a different trend. We used no retinopathy as a reference. Mild NPDR showed the highest risk for progression to the next stage [hazard ratio (HR): 2.00 (95% conference interval (CI): 1.72–2.32)] relative to higher initial grades [HR (moderate NPDR): 1.82 (95% CI: 1.58–2.09) and HR (severe NPDR): 0.87 (95% CI: 0.69–1.09)]. The same trend was observed in the multivariate analysis, in which mild NPDR presented the highest risk for progression to the next stage (adjusted HR (mild NPDR): 1.95 (95% CI: 1.68–2.27), adjusted HR (moderate NPDR): 1.73 (95% CI: 1.50–1.99), and adjusted HR (severe NPDR): 0.82 (95% CI: 0.65–1.03)), (4) Conclusions: Type 2 diabetic patients with earlier-grade DR appeared to exhibit more rapid development to the next grade in our study. As these findings show, more frequent fundus color photography follow-up in earlier-grade DR patients is important to slow DR progression and awaken self-perception.

Myelodysplastic syndrome (MDS) comprised a heterogeneous group of diseases. The prognosis of patients varies even in the same risk groups. Searching for novel prognostic markers is warranted. Leukemic stem cells (LSCs) are responsible for chemoresistance and relapse in leukemia. Recently, expressions of 17 genes related to stemness of LSCs were found to be associated with prognosis in acute myeloid leukemia patients. However, the clinical impact of LSC genes expressions in MDS, a disorder arising from hematopoietic stem cells, remains unclear. We analyzed expression profile of the 17 stemness-related genes in primary MDS patients and identified expression of 4 genes (LAPTM4B, NGFRAP1, EMP1, and CPXM1) were significantly correlated with overall survival (OS). We constructed an LSC4 scoring system based on the weighted sums of the expression of 4 genes and explored its clinical implications in MDS patients. Higher LSC4 scores were associated with higher revised International Prognostic Scoring System (IPSS-R) scores, complex cytogenetics, and mutations in RUNX1, ASXL1, and TP53. High-score patients had significantly shorter OS and leukemia-free survival (LFS), which was also confirmed in 2 independent validation cohorts. Subgroup analysis revealed the prognostic significance of LSC4 scores for OS remained valid across IPSS-R lower- and higher-risk groups. Furthermore, higher LSC4 score was an independent adverse risk factor for OS and LFS in multivariate analysis. In summary, LSC4 score can independently predict prognosis in MDS patients irrespective of IPSS-R risks and may be used to guide the treatment of MDS patients, especially lower-risk group in whom usually only supportive treatment is given.

Purpose:Hepatocellular carcinoma (HCC) is the second leading cause of cancer mortality worldwide. Sleep problems are common in HCC patients and may be attributable to disturbances in the circadian rhythm. Research into the role of circadian rhythms in sleep quality among HCC patients is lacking, however. This study investigated the relationship between the diurnal cortisol profile and sleep quality among HCC patients. We aimed to identify alterations in the diurnal cortisol profile in patients with HCC compared to healthy controls and investigate whether they were associated with poor sleep quality among HCC patients.Methods:Participants comprised 75 HCC patients and 33 healthy individuals. The Taiwanese version of the Pittsburgh Sleep Quality Index (PSQI-T) was administered to assess sleep quality. Saliva samples were collected on 3 consecutive days at five time points daily to measure diurnal cortisol levels.Results:In the HCC group, 89.3% of individuals were poor sleepers (PSQI-T > 5), whereas among healthy individuals, 30.3% were poor sleepers. While the healthy participants’ diurnal cortisol profile followed a typical pattern that peaked 30 min after waking and declined gradually throughout the day, the cortisol level in the HCC patients rebounded at bedtime. Higher cortisol levels were marginally correlated with poor sleep quality ( OR = 1.00007, p < .05).Conclusions:Our study suggests a potential association between disturbed circadian rhythm and poor sleep quality in HCC patients. Further investigation of the causal relationship between sleep and circadian rhythm is warranted.

BACKGROUND Worldwide, proton pump inhibitors (PPIs) are commonly used for the treatment of peptic ulcer and gastro-esophageal reflux disease. Recently, concern has arisen over the potential association between PPIs and hepatocellular carcinoma (HCC). The aim of the current study was to evaluate the influence of PPI use on the risk of HCC, through a systematic review and meta-analysis. METHODS A review of all English-language literature was conducted, using the subject search terms: "hepatocellular carcinoma", "liver cancer", "hepatic tumor", and "proton pump inhibitor" in the major medical databases. A meta-analysis of the qualifying publications was then performed. RESULTS A total of five studies, which had shown that PPIs were associated with HCC (crude risk ratio [RR] = 2.27, 95% confidence interval [CI]: 1.44-3.57; p < 0.01) when an unadjusted RR were adopted, were eligible for meta-analysis. It was observed that the cumulative dose of PPIs may increase the risk of HCC in a linear model (p < 0.01). However, when using data that were adjusted by comorbidities and concurrent medications, the association between PPIs and HCC became insignificant (adjusted RR = 1.62, 95% CI: 0.89-2.93; p = 0.11) and this result was consistent in the sensitivity analysis. CONCLUSION The current meta-analysis has shown that PPI use does not significantly increase the risk of HCC after adjusting for confounding factors. However, further studies are warranted to verify the association between PPIs and HCC in special populations, such as viral or alcoholic liver diseases.

Developmental delay has been associated with inefficient arsenic methylation capacity in preschool children. Folate and vitamin B12 are important nutrients that produce s-adenosylmethionine during single-carbon metabolism and provide methyl groups for arsenic methylation. The aim of the present study was to explore whether plasma folate and vitamin B12 levels influence arsenic methylation capacity and in turn are related to developmental delay in preschool children. A case–control study was conducted in 178 children with developmental delay and 88 normal children, who were recruited from Shin Kong Wu Ho-Su Memorial Teaching Hospital from August 2010 to March 2014. Arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV) in the urine was determined by high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Plasma folate and vitamin B12 levels were measured using a SimulTRAC-SNB radioassay. The results show that the combination of high plasma folate and high vitamin B12 levels were correlated with efficient arsenic methylation capacity (low MMAV %, low InAs %, and high DMAV %). High MMAV % significantly increased and high DMAV % and secondary methylation index decreased the odds ratio (OR) of developmental delay in a dose-dependent manner in both low plasma folate and low vitamin B12 (low/low) groups; the multivariate OR and 95% confidence interval were 5.01 (0.83–30.06), 0.21 (0.04–1.23), and 0.20 (0.03–1.20), respectively. This is the first study to show that the combination of high plasma folate and high vitamin B12 levels increases arsenic methylation capacity and indirectly decreases the OR of developmental delay in preschool children.

Persistent, unresolved inflammation in the liver represents a key trigger for hepatic injury and fibrosis in various liver diseases and is controlled by classically activated pro-inflammatory macrophages, while restorative macrophages of the liver are capable of reversing inflammation once the injury trigger ceases. Here we have identified a novel role for neutrophils as key contributors to resolving the inflammatory response in the liver. Using two models of liver inflammatory resolution, we found that mice undergoing neutrophil depletion during the resolution phase exhibited unresolved hepatic inflammation, activation of the fibrogenic machinery and early fibrosis. These findings were associated with an impairment of the phenotypic switch of pro-inflammatory macrophages into a restorative stage after removal of the cause of injury and an increased NLRP3 / miR-223 ratio. Mice with a deletion of the granulocyte specific miR-223 gene showed a similarly impaired resolution profile that could be reversed by restoring miR-223 levels using a miR-223 3p mimic or infusing neutrophils from wildtype animals. Collectively, our findings reveal a novel role for neutrophils in the liver as resolving effector cells that induce pro-inflammatory macrophages into a restorative phenotype, potentially via miR-223.

This study aimed to determine the interaction of red blood cell cadmium and lead, total urinary arsenic, and plasma selenium in chronic kidney disease (CKD). We recruited 220 CKD patients as well as 438 gender- and age-matched controls, and we defined CKD as 243.90 μg/L) had a significantly lower odds ratio (OR) and 95% confidence interval (CI) (0.23, 0.13–0.42) for CKD compared to those with low plasma selenium levels (≤ 196.70 μg/L). High plasma selenium and low red blood cell cadmium or lead concentrations interacted to decrease the OR and 95% CI for CKD (0.12, 0.06–0.26; 0.09, 0.04–0.19). High plasma selenium and low red blood cell lead levels also interacted to increase the eGFR (20.70, 15.56–26.01 mL/min/1.73 m2). This study is the first to suggest that selenium modifies the eGFR and OR in CKD induced by environmental toxicants.

Background A chronic inflammatory state is a prominent feature in patients with end-stage renal disease (ESRD). Nuclear factor-kappa B (NF-κB) is a transcription factor that regulates the expression of genes involved in inflammation. Some genetic studies have demonstrated that the NF-κB genetic mutation could cause kidney injury and kidney disease progression. However, the association of a gene polymorphism in the transcription factor binding site of NF-κB with kidney disease is not clear. Methods We used the Taiwan Biobank database, the University of California, Santa Cruz, reference genome, and a chromatin immunoprecipitation sequencing database to find single nucleotide polymorphisms (SNPs) at potential binding sites of NF-κB. In addition, we performed a case–control study and genotyped 847 patients with ESRD and 846 healthy controls at Tri-Service General Hospital from 2015 to 2016. Furthermore, we used the ChIP assay to identify the binding activity of different genotypes and used Luciferase reporter assay to examine the function of the rs9395890 polymorphism. Result The results of biometric screening in the databases revealed 15 SNPs with the potential binding site of NF-κB. Genotype distributions of rs9395890 were significantly different in ESRD cases and healthy controls (P = 0.049). The ChIP assay revealed an approximately 1.49-fold enrichment of NF-κB of the variant type TT when compared to that of the wild-type GG in rs9395890 (P = 0.027; TT = 3.20 ± 0.16, GT = 2.81 ± 0.20, GG = 1.71 ± 0.18). The luciferase reporter assay showed that the NF-κB binding site activity in T allele was slightly higher than that in G allele, though it is not significant. Conclusions Our findings indicate that rs9395890 is associated with susceptibility to ESRD in Taiwan population. Electronic supplementary material The online version of this article (10.1186/s12882-019-1471-2) contains supplementary material, which is available to authorized users.

Purpose This study examined the prognostic associations of pre-treatment quality of life (QoL) with overall survival (OS) and distant metastasis-free survival (DFMS) among patients with head and neck cancer (HNC) who underwent free flap reconstruction. Methods A cohort of 127 HNC patients who received free flap reconstruction between November 2010 and June 2014 at a hospital were recruited. Pre-treatment QoL was measured by the University of Washington Quality of Life Questionnaire, which contains six physical domains, including speech, swallowing, appearance, saliva, taste and chewing, as well as the six social-emotional domains of pain, activity, recreation, shoulder, mood, and anxiety. Cox regression analyses were performed. Results Results showed that pre-treatment QoL was predictive of OS and DMFS. Of the domains, swallowing, chewing, speech, taste, saliva, pain and shoulder were demonstrated to be significant predictors of OS. Additionally, swallowing, chewing, speech, pain and activity were demonstrated making significant contributions to DMFS. Conclusion Our data supported that physical domains of pre-treatment QoL were predictors for OS and DFMS in HNC patients with free-flap reconstruction. Longitudinal studies are warranted to clarify the prognostic abilities of social-emotional domains. Information on pre-treatment QoL should be taken into account to individualize care plan for these patients, and hence prolong their survival.

BACKGROUND Antituberculosis (TB) drug-induced liver injury (ATLI) is a common adverse effect of anti-TB drugs. Whether regular monitoring of liver function can ameliorate ATLI has been widely debated. The current study aimed to investigate the liver test monitoring status of patients receiving anti-TB treatment in Taiwan, as well as the impact of scheduled liver function monitoring on the risk of ATLI. METHODS Patients who received anti-TB treatment at our hospital between 2009 and 2017 were enrolled for retrospective analysis. RESULTS A total of 1062 patients were included, and of them 469 (44.2%) received regular liver function monitoring (good monitoring group). ATLI was recognized in 100 (9.4%) patients. The good monitoring group detected more ATLI cases early compared with the poor monitoring group (14.7% vs 5.2%, and 21.4 vs 61.6 days, p < 0.01), with a lower peak serum alanine aminotransferase (276.1 vs 507.1 IU/L, p = 0.05). CONCLUSION In the current study, less than half of all patients who received anti-TB drugs had their liver function monitored regularly. Scheduled monitoring of liver function could facilitate the early identification of more ATLI cases, thus leading to less liver injury. The implementation of periodic liver function monitoring tests in patients receiving anti-TB treatment should be re-emphasized and encouraged.

Objective The association between antipsychotic use and gastric cancer risk remains unclear. Therefore, this study aimed to determine the association between antipsychotic exposure and the incidence of gastric cancer. Methods Using a nested case‐control design, a total of 34 470 gastric cancer patients and 163 430 nongastric cancer controls were identified from Taiwan's National Health Insurance Research Database between 1 January 1997 and 31 December 2013. We analyzed the data using a conditional logistic regression model to adjust for possible confounding variables. Results Antipsychotic use was independently inversely associated with gastric cancer risk after controlling for potential confounding factors including income, urbanization, medications, physical and medical illness, aspirin use, nonsteroidal anti‐inflammatory drug use and triple therapy. In addition, dose‐dependent trends against gastric cancer risk were also shown with individual antipsychotic compounds including thioridazine, haloperidol, sulpiride, clozapine, olanzapine, quetiapine, amisulpride, and risperidone. A sensitivity analysis showed that second‐generation antipsychotics had significant dose‐dependent effects in reducing the risk of gastric cancer risk in patients with and without peptic ulcer disease. Conclusions Antipsychotic use was inversely associated with gastric cancer risk, and dose‐dependent effects against gastric cancer were also seen with several individual antipsychotic compounds.

Inefficient arsenic methylation capacity has been associated with developmental delay in preschool children. Selenium has antioxidant and anti-inflammatory properties that protect experimental animals from chemically induced neurotoxicity. The present study was designed to explore whether plasma selenium levels affects arsenic methylation capacity related to developmental delay in preschool children. A case-control study was conducted from August 2010 to March 2014. All participants were recruited from the Shin Kong Wu Ho-Su Memorial Teaching Hospital. In total, 178 children with a developmental delay and 88 children without a delay were recruited. High-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry were used to determine urinary arsenic species, including arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV). Plasma selenium levels were measured by inductively coupled plasma mass spectrometry. As results, plasma selenium concentration was significantly inversely associated with the odds ratio (OR) of developmental delay. Plasma selenium concentration was positively associated with arsenic methylation capacity [percentage of inorganic arsenic and percentage of MMAV (MMAV%) decreased, and percentage of DMAV (DMAV%) increased]. High plasma selenium concentration and high DMA% significantly and additively interacted to decrease the OR of developmental delay; the OR and 95% confidence interval were 0.40 (0.18-0.90). This is the first study to show a combined dose-response effect of plasma selenium concentration and that efficient arsenic methylation capacity decreased the OR of developmental delay in preschool children.

BACKGROUND Influenza B accounts for approximately one fourth of the seasonal influenza burden. However, research on the importance of influenza B has received less attention compared to influenza A. We sought to describe the association of both coinfections and comorbidities with disease severity among adults presenting to emergency departments (ED) with influenza B. METHODS Nasopharyngeal samples from patients found to be influenza B positive in four US and three Taiwanese ED over four consecutive influenza seasons (2014-2018) were tested for coinfections with the ePlex RP RUO panel. Multivariable logistic regressions were fitted to model adjusted odds ratios (aOR) for two severity outcomes separately: hospitalization and pneumonia diagnosis. Adjusting for demographic factors, underlying health conditions, and the National Early Warning Score (NEWS), we estimated the association of upper respiratory coinfections and comorbidity with disease severity (including hospitalization or pneumonia). RESULTS Amongst all influenza B positive individuals (n = 446), presence of another upper respiratory pathogen was associated with an increased likelihood of hospitalization (aOR = 2.99 [95% confidence interval (95% CI): 1.14-7.85, p = 0.026]) and pneumonia (aOR = 2.27 [95% CI: 1.25-4.09, p = 0.007]). Chronic lung diseases (CLD) were the strongest predictor for hospitalization (aOR = 3.43 [95% CI: 2.98-3.95, p

Background and Aims: The coronavirus disease 2019 (COVID-19) increases hyperinflammatory state, leading to acute lung damage, hyperglycemia, vascular endothelial damage, and a higher mortality rate. Metformin is a first-line treatment for type 2 diabetes and is known to have anti-inflammatory and immunosuppressive effects. Previous studies have shown that metformin use is associated with decreased risk of mortality among patients with COVID-19, however, the results are still inconclusive. This study investigated the association between metformin and the risk of mortality among diabetes patients with COVID-19. Methods: Data were collected from online databases such as PubMed, EMBASE, Scopus, and Web of Science, and reference from the most relevant articles. The search and collection of relevant articles was carried out between 1 February 2020, and 20 June 2021. Two independent reviewers extracted information from selected studies. The random-effects model was used to estimate risk ratios (RRs), with a 95% confidence interval. Results: A total of 16 studies met all inclusion criteria. Diabetes patients given metformin had a significantly reduced risk of mortality ((RR 0.65, 95% CI: 0.54–0.80, p &lt, 0.001, heterogeneity I2 = 75.88, Q = 62.20, and τ2 = 0.06, p &lt, 0.001)) compared with those who were not given metformin. Subgroup analyses showed that the beneficial effect of metformin was higher in the patients from North America (RR 0.43, 95% CI: 0.26–0.72, p = 0.001, heterogeneity I2 = 85.57, Q = 34.65, τ2 = 0.31) than in patients from Europe (RR 0.67, 95% CI: 0.47–0.94, p = 0.02, heterogeneity I2 = 82.69, Q = 23.11, τ2 = 0.10) and Asia (RR 0.90, 95% CI: 0.43–1.86, p = 0.78, heterogeneity I2 = 64.12, Q = 11.15, τ2 = 0.40). Conclusion: This meta-analysis shows evidence that supports the theory that the use of metformin is associated with a decreased risk of mortality among diabetes patients with COVID-19. Randomized control trials with a higher number of participants are warranted to assess the effectiveness of metformin for reducing the mortality of COVID-19 patients.

The incidence of oral cavity squamous cell carcinoma (OSCC) is particularly high in South Asia. According to the National Comprehensive Cancer Network, OSCC can arise in several subsites. We investigated survival rates and the clinical and pathological characteristics of OSCC in different anatomical subsites in the Taiwanese population. We retrospectively analyzed data for 3010 patients with OSCC treated at the Changhua Christian Hospital. Subsequently, we compared clinical and pathological features of OSCC in different subsites. Pathological T4 stage OSCCs occurred in the alveolar ridge and retromolar trigone in 56.4% and 43.7% of cases, respectively. More than 25% of patients with tongue OSCC and 23.4% of those with retromolar OSCC had lymph node metastasis. The prognosis was worst for hard palate OSCC (hazard ratio 1.848; p p = 0.017). Retromolar OSCC recurred most often and tongue OSCC second most often. The risk for cancer-related mortality was highest for hard palate OSCC, followed by alveolar ridge and retromolar OSCC. We found distinct differences in survival among the different subsites of OSCC. Our findings may also help prompt future investigations of OSCC in different subsites in Taiwanese patients.

Background: glycated hemoglobin (HbA1c) provides information on diabetes mellitus (DM) management. Electrocardiography (ECG) is a noninvasive test of cardiac activity that has been determined to be related to DM and its complications. This study developed a deep learning model (DLM) to estimate HbA1c via ECG. Methods: there were 104,823 ECGs with corresponding HbA1c or fasting glucose which were utilized to train a DLM for calculating ECG-HbA1c. Next, 1539 cases from outpatient departments and health examination centers provided 2190 ECGs for initial validation, and another 3293 cases with their first ECGs were employed to analyze its contributions to DM management. The primary analysis was used to distinguish patients with and without mild to severe DM, and the secondary analysis was to explore the predictive value of ECG-HbA1c for future complications, which included all-cause mortality, new-onset chronic kidney disease (CKD), and new-onset heart failure (HF). Results: we used a gender/age-matching strategy to train a DLM to achieve the best AUCs of 0.8255 with a sensitivity of 71.9% and specificity of 77.7% in a follow-up cohort with correlation of 0.496 and mean absolute errors of 1.230. The stratified analysis shows that DM presented in patients with fewer comorbidities was significantly more likely to be detected by ECG-HbA1c. Patients with higher ECG-HbA1c under the same Lab-HbA1c exhibited worse physical conditions. Of interest, ECG-HbA1c may contribute to the mortality (gender/age adjusted hazard ratio (HR): 1.53, 95% conference interval (CI): 1.08–2.17), new-onset CKD (HR: 1.56, 95% CI: 1.30–1.87), and new-onset HF (HR: 1.51, 95% CI: 1.13–2.01) independently of Lab-HbA1c. An additional impact of ECG-HbA1c on the risk of all-cause mortality (C-index: 0.831 to 0.835, p &lt, 0.05), new-onset CKD (C-index: 0.735 to 0.745, p &lt, 0.01), and new-onset HF (C-index: 0.793 to 0.796, p &lt, 0.05) were observed in full adjustment models. Conclusion: the ECG-HbA1c could be considered as a novel biomarker for screening DM and predicting the progression of DM and its complications.

The world's population is aging, and the prevalence of hip fracture is rising. Vitamin D deficiency is a risk factor for hip fracture and predicts functional recovery and survival following hip fracture surgery. This cross-sectional study identified the prevalence of vitamin D deficiency in Taiwanese older patients with hip fracture and potential risk factors for vitamin D deficiency. Data from older adults with hip fracture admitted to a single medical center in Taipei, Taiwan were prospectively collected. The preoperative serum 25-hydroxyvitamin D [25(OH)D] concentration and comprehensive clinical history of each patient were examined. A multinomial logistic regression model was used to compare the clinical characteristics of deficient, insufficient, and sufficient 25(OH)D concentration groups. The cohort comprised 310 older adults with hip fracture. The mean age was 80±10 y. The deficient, insufficient, and sufficient groups comprised 180, 84, and 46 patients (58.1%, 27.1%, and 14.8%), respectively. Univariate analysis revealed significant intergroup differences in serum albumin level and body fat percentage and marginally significant differences in serum albumin, estimated glomerular filtration rate, body mass index, and comorbidities of affective or psychotic disorders. In the multinomial logistic regression model, albumin level was the only factor significantly correlated with higher 25(OH)D concentrations in the sufficient and insufficient groups compared with the deficient group. No variable, including preinjury functional status, was significantly correlated with vitamin D deficiency except malnutrition. Our findings may aid the establishment of a robust screening and treatment program for vitamin D deficiency.

OBJECTIVES Sulfamethoxazole-trimethoprim (SMX-TMP) is one of the most frequently used antibiotics. SMX is metabolized by N-acetyltransferase (NAT) and cytochrome P450 2C9 (CYP2C9) to nontoxic or toxic intermediates. Little is known about the association between genetic variations of these enzymes and SMX-TMP-induced liver injury (SILI). The aim of this study was to explore the genetic polymorphisms of NAT2 and CYP2C9 and the susceptibility to SILI in a Han Chinese population. METHODS A total of 158 patients with SILI and 145 controls were recruited in this study. PCR-based genotyping with matrix-assisted laser desorption ionization-time of flight was used to assay the major NAT2 and CYP2C9 genotypes including NAT2 rs1495741, rs1041983, rs1801280, CYP2C9 rs1799853, rs1057910 and rs4918758. RESULTS The SILI group had a higher frequency of the NAT2 rs1495741 variant AA genotype and rs1041983 variant TT genotype than the controls (42.4 vs. 25.5%; P = 0.008, and 40.5 vs. 25.5%; P = 0.022, respectively). The SILI group had more slow acetylators than the controls (43.7 vs. 25.5%; P = 0.001). There were no significant differences in the genetic variations of CYP2C9 between the SILI and control groups. After adjusting for confounding factors, the NAT2 slow acetylators still had an increased risk of SILI (adjusted OR: 2.49; 95% confidence interval: 1.46-4.24; P = 0.001), especially in those with hepatocellular and mixed type SILI. CONCLUSIONS NAT2 slow acetylators are associated with a higher risk of SILI in the Han Chinese population. However, CYP2C9 genetic polymorphisms are not associated with the susceptibility to SILI.

Background Although prior literature suggests that metoprolol may worsen glucose control compared to carvedilol, whether this has clinical relevance among older adults with diabetes and heart failure remains an open question. Methods This was a US retrospective cohort study utilizing data sourced from a 50% national sample of Medicare fee-for-service claims of patients with Part D prescription drug coverage (2007-2017). Among patients with diabetes and heart failure we identified initiators of metoprolol or carvedilol, which were 1:1 propensity score matched on >90 variables. The primary outcome was initiation of a new oral or injectable antidiabetic medication (proxy for uncontrolled diabetes); secondary outcomes included initiation of insulin and severe hyperglycemic event (composite of emergency room visits or hospitalizations related to hyperglycemia). Results Among 24 239 propensity score-matched pairs (mean [SD] age 77.7 [8.0] year; male (39.1%)), there were 8150 [incidence rate per 100 person-years (IR) = 33.5] episodes of antidiabetic medication initiation among metoprolol users (exposure arm) compared to 8576 [IR = 33.4] among carvedilol users (comparator arm) compared to corresponding to an adjusted hazard ratio [aHR] of 0.97 (95% CI: 0.94, 1.01). Similarly, metoprolol was not associated with a significant increase in the risk of secondary outcomes including insulin initiation: aHR of 0.98 (95% CI: 0.93, 1.04)) and severe hyperglycemic events: aHR of 0.98 (95% CI: 0.93, 1.02). Conclusions In this large study of older adults with heart failure and diabetes, initiation of metoprolol compared to carvedilol was not associated with an increase in the risk of clinically relevant hyperglycemia. This article is protected by copyright. All rights reserved.

Background Statins are widely used to treat people with metabolic and cardiovascular disorders. The effect of statins on coronavirus disease 2019 (COVID-19) is unclear. To investigate the association between statins and COVID-19 outcomes and, if possible, identify the subgroup population that benefits most from statin use. Materials and methods A systematic review and meta-analysis of published studies that included statin users and described COVID-19 outcomes through 10 November 2020. This study used the generic inverse variance method to perform meta-analyses with random-effects modelling. The main outcomes were evaluation of the need for invasive mechanical ventilator (IMV) support, the need for intensive care unit (ICU) care and death. All outcomes were measured as dichotomous variables. Results A total of 28 observational studies, covering data from 63,537 individuals with COVID-19, were included. The use of statins was significantly associated with decreased mortality (odds ratio [OR] = 0.71, 95% confidence interval [CI]: 0.55–0.92, I2=72%) and the need for IMV (OR = 0.81, 95% CI: 0.69–0.95, I2=0%) but was not linked to the need for ICU care (OR = 0.91, 95% CI: 0.55–1.51, I2=66%). Subgroup analysis further identified five types of studies in which statin users had even lower odds of death. Conclusions The use of statins was significantly associated with a reduced need for IMV and decreased mortality among individuals with COVID-19. Statins may not need to be discontinued because of concern for COVID-19 on admission. Further randomized controlled trial (RCTs) are needed to clarify the causal effect between statin use and severe COVID-19 outcomes.Key messagesParticipants in five types of studies were shown to have even lower odds of death when taking statins.The use of statins was significantly associated with a reduced need for invasive mechanical ventilation and decreased all-cause mortality among individuals with COVID-19. However, statin use did not prevent participants from needing care in the intensive care unit.The results justify performing randomized controlled trials (RCTs) to validate the benefits of statins on COVID-19 outcomes.

Key Points CIBERSORTx analytical approach reveals M0, M2, and eosinophil fractions in the BM to be the most relevant prognostic factors in patients with MDS.High-risk immune cell scores correlate with NF-κB signaling, oxidative stress, and leukemic stem cell signature pathways., Visual Abstract, Aside from cell intrinsic factors such as genetic alterations, immune dysregulation in the bone marrow (BM) microenvironment plays a role in the development and progression of myelodysplastic syndromes (MDS). However, the prognostic implications of various immune cells in patients with MDS remain unclear. We adopted CIBERSORTx to estimate the relative fractions of 22 subtypes of immune cells in the BM of 316 patients with MDS and correlated the results with clinical outcomes. A lower fraction of unpolarized M0 macrophages and higher fractions of M2 macrophages and eosinophils were significantly associated with inferior survival. An immune cell scoring system (ICSS) was constructed based on the proportion of these 3 immune cells in the BM. The ICSS high-risk patients had higher BM blast counts, higher frequencies of poor-risk cytogenetics, and more NPM1, TP53, and WT1 mutations than intermediate- and low-risk patients. The ICSS could stratify patients with MDS into 3 risk groups with distinct leukemia-free survival and overall survival among the total cohort and in the subgroups of patients with lower and higher disease risk based on the revised International Prognostic Scoring System (IPSS-R). The prognostic significance of ICSS was also validated in another independent cohort. Multivariable analysis revealed that ICSS independently predicted prognosis, regardless of age, IPSS-R, and mutation status. Bioinformatic analysis demonstrated a significant correlation between high-risk ICSS and nuclear factor κB signaling, oxidative stress, and leukemic stem cell signature pathways. Further studies investigating the mechanistic insight into the crosstalk between stem cells and immune cells are warranted.

The metabolically healthy obese (MHO) characterized by the absence of metabolic syndrome have shown superior cardiorespiratory fitness (CRF) and similar muscular strength as compared with the metabolically unhealthy obese (MUO). However, this finding might be biased by the baseline sedentary behavior in the general population. This study utilized 3669 physically active military males aged 18–50 years in Taiwan. Obesity and metabolically unhealthy were respectively defined as body mass index ≥ 27.5 kg/m2 and presence of at least two major components of the metabolic syndrome, according to the International Diabetes Federation criteria for Asian male adults. Four groups were accordingly classified as the metabolically healthy lean (MHL, n = 2510), metabolically unhealthy lean (MUL, n = 331), MHO (n = 181) and MUO (n = 647). CRF was evaluated by time for a 3-km run, and muscular strengths were separately assessed by numbers of push-up and sit-up within 2 min. Analysis of covariance was utilized to compare the difference in each exercise performance between groups adjusting for age, service specialty, smoking, alcohol intake and physical activity. The metabolic syndrome prevalence in MUL and MUO was 49.8% and 47.6%, respectively. The performance of CRF did not differ between MHO and MUO (892.3 ± 5.4 s and 892.6 ± 3.0 s, p = 0.97) which were both inferior to MUL and MHL (875.2 ± 4.0 s and 848.6 ± 1.3 s, all p values p = 0.78) which were both less than MHO and MHL (48.4 ± 0.8 and 50.6 ± 0.2, all p values p values

BACKGROUND AND OBJECTIVE: Systematic reviews and meta-analyses of direct oral anticoagulants (DOACs) for patients with chronic kidney disease (CKD) or dialysis patients are lacking. We aimed to compare the efficacy and safety of DOACs and warfarin in patients with CKD requiring anticoagulation therapy.We performed a systematic review and meta-analysis of six randomized controlled trials and 19 observational studies, with the inclusion criteria being a comparative study between DOACs and warfarin in patients with CKD or dialysis patients from database inception until August 2020. The efficacy outcomes were stroke, systemic embolism (SE), or venous thromboembolism (VTE), and the safety outcome was major bleeding.Compared with warfarin, DOACs significantly reduced the risk of stroke/SE/VTE by 22% (hazard ratio [HR] = 0.78, 95% confidence interval [CI] 0.64-0.95) and major bleeding by 17% (HR = 0.83, 95% CI 0.71-0.97). On comparing factor Xa inhibitors and dabigatran with warfarin separately, factor Xa inhibitors significantly reduced the risk of stroke/SE/VTE (HR = 0.78, 95% CI 0.62-0.98) and major bleeding (HR = 0.76, 95% CI 0.64-0.91) overall in patients. Comparing each DOACs with warfarin separately, apixaban was associated with a significantly better risk reduction of stroke/SE/VTE (25% risk reduction) and major bleeding (35% risk reduction) than warfarin. Compared with warfarin, DOACs significantly reduced the risk of stroke, SE, or VTE by 19% (HR = 0.81, 95% CI 0.68-0.97) in patients with CKD stage 3 and significantly lowered the risk of major bleeding by 31% (HR = 0.69, 95% CI 0.56-0.85) in patients with CKD stages 4-5.In pooled, analyzed randomized controlled trials and observational studies, DOACs were associated with better efficacy in early CKD, as well as similar efficacy and safety outcomes to warfarin in patients with CKD stages 4-5 or dialysis patients. The results of patients with CKD stages 4-5 and dialysis patients were from observational studies. Well-designed randomized controlled trials focused on DOAC use in patients with CKD and dialysis patients are needed. PROSPERO register number: CRD42020150599, 6 February, 2020.

Coronavirus disease 2019 (COVID-19) has already raised serious concern globally as the number of confirmed or suspected cases have increased rapidly. Epidemiological studies reported that obesity is associated with a higher rate of mortality in patients with COVID-19. Yet, to our knowledge, there is no comprehensive systematic review and meta-analysis to assess the effects of obesity and mortality among patients with COVID-19. We, therefore, aimed to evaluate the effect of obesity, associated comorbidities, and other factors on the risk of death due to COVID-19. We did a systematic search on PubMed, EMBASE, Google Scholar, Web of Science, and Scopus between January 1, 2020, and August 30, 2020. We followed Cochrane Guidelines to find relevant articles, and two reviewers extracted data from retrieved articles. Disagreement during those stages was resolved by discussion with the main investigator. The random-effects model was used to calculate effect sizes. We included 17 articles with a total of 543,399 patients. Obesity was significantly associated with an increased risk of mortality among patients with COVID-19 (RRadjust: 1.42 (95%CI: 1.24–1.63, p < 0.001). The pooled risk ratio for class I, class II, and class III obesity were 1.27 (95%CI: 1.05–1.54, p = 0.01), 1.56 (95%CI: 1.11–2.19, p < 0.01), and 1.92 (95%CI: 1.50–2.47, p < 0.001), respectively). In subgroup analysis, the pooled risk ratio for the patients with stroke, CPOD, CKD, and diabetes were 1.80 (95%CI: 0.89–3.64, p = 0.10), 1.57 (95%CI: 1.57–1.91, p < 0.001), 1.34 (95%CI: 1.18–1.52, p < 0.001), and 1.19 (1.07–1.32, p = 0.001), respectively. However, patients with obesity who were more than 65 years had a higher risk of mortality (RR: 2.54; 95%CI: 1.62–3.67, p < 0.001). Our study showed that obesity was associated with an increased risk of death from COVID-19, particularly in patients aged more than 65 years. Physicians should aware of these risk factors when dealing with patients with COVID-19 and take early treatment intervention to reduce the mortality of COVID-19 patients.

Bacterial vaginosis (BV) is the most common vaginal infection globally, with a high recurrent rate after antibiotic treatment. Probiotics consumption is known to improve BV with different efficacy among species or strains. After in vitro selection of Lactobacillus strains with growth inhibition and preventing adhesion to HeLa cervical epithelial cells, a randomized and double-blinded trial of two Lactobacillus formula, namely, VGA-1 and VGA-2, in BV patients with Nugent scores of 4&ndash, 10 was conducted. Among 37 subjects who completed the trial, we observed significantly decreased Nugent scores in both VGA-1 (n = 18) and VGA-2 (n = 19) consumption groups. VGA-1 consumption significantly improved vaginal discharge odor/color and itching at both 2-week and 4-week-consumption, but those only observed after a 4-week-consumption in the VGA-2 group. We also observed a tendency to reduce recurrent rates among enrolled participants after VGA-1 or VGA-2 consumption. The improvement effect of VGA-1/VGA-2 was associated with the significant reduction of interleukin-6 expression after 4-week-consumption and the restoration of normal vaginal microflora by quantitative polymerase chain reaction analysis. In conclusion, VGA-1 or VGA-2 displayed beneficial effects in BV patients, but the VGA-1 formula showed a better efficacy, potentially used for BV intervention.

(1) Background: It has rarely been studied whether the severity of diabetic retinopathy (DR) could influence renal disease progression in end-stage renal disease (ESRD) and chronic kidney disease (CKD) in patients with type 2 diabetes. The aim of this study was to evaluate renal disease progression in ESRD and CKD according to DR severity in patients with type 2 diabetes. (2) Methods: We included 1329 patients and divided the cohort into two end-points. The first was to trace the incidence of ESRD in all enrolled participants and the other was to follow their progression to CKD. (3) Results: Significantly higher crude hazard ratios (HRs) of ESRD incidence in all enrolled participants were noted, and this ratio increased in a stepwise fashion. However, after adjustment, DR severity was not associated with ESRD events. Therefore, a subgroup of 841 patients without CKD was enrolled to track their progression to CKD. Compared with no diabetic retinopathy, the progression of CKD increased in a stepwise fashion, from mild nonproliferative diabetic retinopathy (NPDR) to moderate NPDR, to severe NPDR and to proliferative diabetic retinopathy (PDR), both in the crude and adjusted models. (4) Conclusions: The severity of retinopathy appeared to be associated with renal lesions and the development of CKD. Our findings suggest that the severity of DR is a risk factor for progression to CKD. Therefore, diabetic retinopathy is useful for prognosticating the clinical course of diabetic kidney disease.

Objective This study aimed to create a prediction model with a radiographic score, serum, and cerebrospinal fluid (CSF) values for the occurrence of shunt-dependent hydrocephalus (SDHC) in patients with aneurysmal subarachnoid hemorrhage (aSAH) and to review and analyze literature related to the prediction of the development of SDHC. Methods Sixty-three patients with aSAH who underwent external ventricular drain insertion were included and separated into 2 subgroups: non-SDHC and SDHC. Patient characteristics, computed tomography scoring system, and serum and CSF parameters were collected. Multivariate logistic regression was conducted to illustrate a nomogram for determining the predictors of SDHC. Furthermore, we sorted and summarized previous meta-analyses for predictors of SDHC. Results The SDHC group had 42 cases. Stepwise logistic regression analysis revealed 3 independent predictive factors associated with a higher modified Graeb (mGraeb) score, lower level of estimated glomerular filtration rate group, and lower level of CSF glucose. The nomogram, based on these 3 factors, was presented with significant predictive performance (area under curve = 0.895) for SDHC development, compared with other scoring systems (AUC = 0.764–0.885). In addition, a forest plot was generated to present the 12 statistically significant predictors and odds ratio for correlations with the development of SDHC. Conclusions First, the development of a nomogram with combined significant factors had a good performance in estimating the risk of SDHC in primary patient evaluation and assisted in clinical decision making. Second, a narrative review, presented with a forest plot, provided the current published data on predicting SDHC.

The present study aimed to investigate the effect of oral resveratrol supplementation on the key molecular gene expressions involved in mitochondria biogenesis and glycogen resynthesis in human skeletal muscle. Nine young male athletes participated in the single-blind and crossover designed study. All subjects completed a 4-day resveratrol and placebo supplement in a randomized order while performing a single bout of cycling exercise. Immediately after the exercise challenge, the subjects consumed a carbohydrate (CHO) meal (2 g CHO/Kg body mass) with either resveratrol or placebo capsules. Biopsied muscle samples, blood samples and expired gas samples were obtained at 0 h and 3 h after exercise. The muscle samples were measured for gene transcription factor expression by real-time PCR for glucose uptake and mitochondria biogenesis. Plasma glucose, insulin, glycerol, non-esterified fatty acid concentrations and respiratory exchange ratio were analyzed during post-exercise recovery periods. The results showed that the muscle glycogen concentrations were higher at 3 h than at 0 h, however, there were no difference between resveratrol trial and placebo trial. There were no significantly different concentrations in plasma parameters between the two trials. Similarly, no measured gene expressions were significant between the two trials. The evidence concluded that the 4-day oral resveratrol supplementation did not improve post-exercise muscle glycogen resynthesis and related glucose uptake and mitochondrial biosynthesis gene expression in men.

Background The survival rates of advanced cancer patients remain low despite clinical therapy advancements. However, physical activity showed promising effects in improving cancer outcomes. This review aimed to systematically evaluate and synthesize the effects on overall mortality of post-diagnosis physical activity in advanced cancer patients. Methods A systematic search of six English databases (PubMed, EMBASE, CINAHL, PsycINFO, The Cochrane Central Register of Controlled Trials, and SPORTDiscus) was conducted from their inception up to 3 February 2021. The association of physical activity with survival was evaluated by combining study-specific hazard ratios with random-effects meta-analysis models. Results Eleven studies were identified. Compared with the reference group, higher-level physical activity was not significantly associated with a lower risk of earlier mortality in advanced cancer patients (InHR = − 0.18, 95% CI, − 0.36 to 0.01). When separated by study type, a higher level of physical activity in non-randomised trials was significantly associated with reduced mortality risk (InHR = − 0.25, 95% CI: − 0.44, − 0.06). However, in randomised trials, engaging in exercise was not significantly associated with a lower mortality risk compared with the control group (InHR = 0.08, 95%CI: − 0.17, 0.32). Conclusions Discrepancies were uncovered in the effect of physical activity on overall survival in randomised and non-randomised trials. In non-randomised trials, a higher level of physical activity was significantly associated with a lower risk of mortality, whereas no significant effect on survival was observed during exercise interventions compared to the control in randomised trials. Considering the wider benefits of physical activity, exercise can still be recommended to improve outcomes for advanced cancer patients. Nevertheless, it might be too late for advanced cancer patients to start exercising for survival improvements, based on findings from randomised controlled trials.

Statins constitute the mainstay treatment for atherosclerotic cardiovascular disease, which is associated with the risk of new-onset diabetes mellitus (NODM). However, the effects of individual statins on the risk of NODM remain unclear. We recruited 48,941 patients taking one of the three interested statins in a tertiary hospital between 2006 and 2018. Among them, 8337 non-diabetic patients taking moderate-intensity statins (2 mg/day pitavastatin, 10 mg/day atorvastatin, and 10 mg/day rosuvastatin) were included. The pitavastatin group had a higher probability of being NODM-free than the atorvastatin and rosuvastatin groups during the 4-year follow-up (log-rank test: p = 0.038). A subgroup analysis revealed that rosuvastatin had a significantly higher risk of NODM than pitavastatin among patients with coronary artery disease (CAD) (adjusted HR [aHR], 1.47, 95% confidence interval [CI], 1.05&ndash, 2.05, p = 0.025), hypertension (aHR, 1.26, 95% CI, 1.00&ndash, 1.59, p = 0.047), or chronic obstructive pulmonary disease (COPD) (aHR, 1.74, 95% CI, 1.02&ndash, 2.94, p = 0.04). We concluded that compared with rosuvastatin, reduced diabetogenic effects of pitavastatin were observed among patients treated with moderate-intensity statin who had hypertension, COPD, or CAD. Additional studies are required to prove the effects of different statins on the risk of NODM.

BackgroundThe initial detection and diagnosis of ST-segment or non-ST-segment elevation myocardial infarction (STEMI or NSTEMI) definitely rely on a 12-lead electrocardiogram (ECG). Delay or misdiagnosis is not unusual by subjective interpretation. Our aim is to develop a DLM as a diagnostic support tool to detect MI based on a 12-lead ECG and to evaluate the performance of this model.MethodsThis study included 1,051 ECGs from 737 coronary angiography (CAG)-validated STEMI patients, 697 ECGs from 287 CAG-validated NSTEMI patients, and 140,336 not-MI ECGs from 76,775 patients at emergency departments. DLM was trained and validated for the performance using 80% and 20% of the ECGs, respectively. A human-machine competition was conducted. The area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were used to evaluate the performance of DLM and experts. STEMI versus not-STEMI, and MI versus not-MI were evaluated by DLM.ResultsThe AUCs of DLM for identifying STEMI and MI were 0.976 and 0.944 in the human-machine competition, respectively, which were significantly better than those of our best clinicians. In the real world setting, DLM presented with AUC of 0.995/0.916 with corresponding sensitivities of 96.9%/77.0%, and specificities of 96.2%/92.9% in the identification of STEMI and MI, respectively. Furthermore, DLM demonstrated sufficient diagnostic capacity for STEMI without the aid of troponin I (TnI) (AUC= 0.996) with corresponding sensitivity and specificity of 98.4% and 96.9%. The AUC of combined DLM and the first recorded TnI for the detection of NSTEMI were increased to 0.978 with corresponding sensitivity and specificity of 91.6% and 96.7%, which was better than that of DLM (0.877) or TnI (0.949) alone. ConclusionsDLM may serve as a diagnostic decision tool to assist intensive or emergency medical system-based networks and frontline physicians in identifying STEMI and NSTEMI in a timely and precise manner to prevent delay or misdiagnosis, and thereby to facilitate subsequent reperfusion therapy.

In fiscal year (FY) 2016, the U.S. transitioned to the ICD-10, which includes eight times more amputation procedure codes than the ICD-9. To evaluate trends over time, researchers need assurance that differences over time are not influenced by a change in the coding system. Thus, we aimed to compare the diagnostic accuracy for ascertaining amputations performed during the ICD-9 era compared with during the ICD-10 era, using medical record review as a gold standard. This information will be valuable for others who use electronic health records to study lower-extremity amputation and whose data span this transition. The source population was veterans who had a procedure code (ICD or Current Procedural Terminology [CPT]) for an initial toe or ray amputation (hereafter referred to as toe amputations) between FY 2005 and FY 2016 and a diagnosis of diabetes or prescription for a diabetes medication in the year prior to their toe amputation (1). We randomly sampled 150 veterans from the parent study (1) who had initial toe amputations in FY 2014 and follow-up through the end of FY 2015 (during the ICD-9 era) and 150 veterans who had initial toe amputations in FY 2016 (during the ICD-10 era). The outcome of interest was an ipsilateral amputation (at any level) in the year after the toe amputation. Procedure codes were extracted from the Veterans Affairs (VA) Corporate Data Warehouse, which includes data from the VA electronic medical record. To maximize sensitivity for the parent study, we relied on both ICD and CPT codes for identification …