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BACKGROUND: Early recognition of severe COVID-19 is essential for timely patient triage. AIMS: We aim to report clinical and laboratory findings and patient outcomes at a tertiary hospital in Melbourne, Australia. METHODS: This is a retrospective study of adult inpatients with COVID-19 admitted to Northern Health from March to September 2020. Data were extracted from electronic medical records. RESULTS: Key admission data was available for 182 patients (median age 67.0 years (interquartile range, 47.9-83.1; 51.1% female). 56 (30.8%) were from residential care. 117 (64.3%) patients were assigned Goals-of-Patient-Care (GOPC) A or B and 65 (35.7%) GOPC C or D. Comorbidities were present in 135 patients (74.2%). 63.2% of patients received antibiotics, 6.6% had antivirals, 45.6% received systemic glucocorticoid and 3.3% had tocilizumab. 56 (30.8%) developed clinical deterioration (24 requiring ventilation, 21 receiving critical care, 34 died). Overall, in-hospital clinical deterioration was significantly associated with older age (p

Atherosclerosis serves as the pathological basis of most cardiovascular and cerebrovascular diseases. C1q tumor necrosis factor-related protein (CTRP1) is a 35-kDa glycoprotein synthesized by various tissues and cells, such as adipose tissue and macrophages. As an adiponectin paralog, CTRP1 signals through adiponectin receptor 1 (AdipoR1) and participates in a variety of pathophysiological processes. Circulating CTRP1 levels are significantly increased in patients with coronary artery disease. Importantly, CTRP1 was shown to accelerate the development of atherosclerosis by promoting vascular inflammation, macrophage foam cell formation and endothelial barrier dysfunction. This review focused on recent advances regarding the role of CTRP1 in atherogenesis with an emphasis on its potential as a novel biomarker and a promising therapeutic target for atherosclerosis-related diseases.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors might increase the risk of intestinal obstruction, but real-world evidence for this severe adverse event is lacking. Thus, the objective of this study was to determine whether GLP-1 RAs and DPP-4 inhibitors are associated with an increased risk of intestinal obstruction compared with sodium-glucose cotransporter-2 (SGLT-2) inhibitors. We used the United Kingdom Clinical Practice Research Datalink and linked databases to assemble two new-user, active comparator cohorts (2013-2019). The first included 25,617 and 67,261 GLP-1 RA and SGLT-2 inhibitor users, respectively. The second included 131,927 and 40,615 DPP-4 inhibitor and SGLT-2 inhibitor users, respectively. Propensity score fine stratification weighted Cox proportional hazards models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of intestinal obstruction requiring hospitalization. GLP-1 RAs were associated with an increased risk of intestinal obstruction compared with SGLT-2 inhibitors (1.9 vs. 1.1 per 1,000 person-years, respectively; HR: 1.69, 95% CI: 1.04-2.74). The highest HR was observed after 1.6 years of use (HR: 3.48, 95% CI: 1.79-6.79). DPP-4 inhibitors were also associated with an increased risk (2.7 vs. 1.0 per 1,000 person-years; HR: 2.59, 95% CI: 1.52-4.42), with the highest HR observed after 1.8 years of use (HR: 9.53, 95% CI: 4.47-20.30). The number needed to harm after 1 year of use was 1,223 and 603 for GLP-1 RAs and DPP-4 inhibitors, respectively. In this large real-world study, GLP-1 RAs and DPP-4 inhibitors were associated with an increased risk of intestinal obstruction.

Objective To observe the clinical effect of quick puncture with collateral-pricking cupping for facial acne. Methods Twenty-eight patients with acne were treated with pricking acne spot and abdominal region of three toes for bloodletting combined with collateral-pricking cupping on the back, once every 5 days, for 3 weeks in succession. A 3-month follow-up was applied to observe the reducing rate and clinical effect of facial skin lesions after treatment. Results Of the 28 cases, 9 were cured, 12 remarkably effective, 5 effective, and 2 ineffective. The total effective rate was 92.86%. Conclusion The effect of pricking acne spot and abdominal region of three toes combined with collateral-pricking cupping on the back is good, being worthy of further clinical discussion to promote its application.

Risk assessment for venous thromboembolism in pregnancy and the puerperium is currently limited to stratifying clinical surrogate risk factors without high-quality evidence. While the absolute risk of pregnancy-associated venous thromboembolism is low for the vast majority of women, associated morbidity and mortality remains significant. As guidelines for thromboprophylaxis vary widely, some women may be under- or over-anticoagulated, contributing to poor outcomes. New global coagulation assays provide a holistic view of coagulation and may have the potential to detect hypercoagulability in pregnancy, unlike clinically available coagulation assays. However, there are major technical challenges to overcome before global coagulation assays can be realistically proposed as an adjunct to risk assessment for pregnancy-associated venous thromboembolism. This review summarises the literature and controversies in the prediction and prevention of pregnancy-associated venous thromboembolism and outlines the new tools in haematology that may assist in our future understanding of hypercoagulability in pregnancy.

Aims To determine whether adiposity modified the effect on the cardiovascular safety of sulfonylureas as a first-line therapy compared with metformin among patients with type 2 diabetes. Materials and methods Using the UK Clinical Practice Research Datalink, we conducted a cohort study among 13 862 new sulfonylurea users matched on body mass index (BMI) and propensity score, in a 1:1 ratio, to new metformin users between April 1, 1998 and December 31, 2016. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of major adverse cardiovascular events (MACE), individual components of MACE (myocardial infarction, ischemic stroke, cardiovascular mortality), and all-cause mortality, comparing use of sulfonylureas with use of metformin overall, and within BMI categories (≤ 24.9 kg/m2 , 25.0-29.9 kg/m2 , ≥ 30 kg/m2 ). Results Compared with metformin, sulfonylureas were not associated with an increased risk of MACE either overall (HR: 1.08; 95% CI: 0.94-1.23) or by BMI categories. Similar findings were observed for myocardial infarction and ischemic stroke. In contrast, sulfonylureas were associated with an increased risk of cardiovascular mortality (HR: 1.24; 95% CI: 1.04-1.48), primarily among obese patients (HR: 1.52; 95% CI: 1.08-2.13), and not among normal-weight patients (HR: 1.00; 95% CI: 0.72-1.39; p-interaction: 0.21). Similar results were observed for all-cause mortality (HR: 1.47; 95% CI: 1.32-1.62), where an increased risk was observed among obese patients (HR: 1.83; 95% CI: 1.49-2.25), but not normal-weight patients (HR: 1.18; 95% CI: 0.99-1.42; p-interaction: 0.006). Conclusion The findings of this study suggest that adiposity may have a modifying effect on the association between sulfonylureas and cardiovascular and all-cause mortality compared with metformin. This article is protected by copyright. All rights reserved.

The major pathologic hallmark of the alcoholic liver disease (ALD) is the representation of chronic alcohol-induced hepatocyte lipid accumulation. This study aims to investigate the hepatoprotective role of triterpenoids-enriched extracts from Antrodia cinnamomea mycelia (ACT) in chronic alcohol-induced liver injury mice, establishing in C57BL/6 mice through gradient alcohol feeding for 24 weeks. In long-term alcohol consumption mice, the significantly lost body weight, increased organ indexes, hepatic alanine aminotransferase and aspartate aminotransferase levels were all remissed after 6-week ACT orally administration, showing its hepatoprotective property. ACT suppressed the triglyceride, total cholesterol and low-density lipoprotein levels, and enhanced high-density lipoprotein levels in serum or/and liver of chronic alcohol damaged mice. Combining with the pathological observations, ACT displayed an anti-steatosis effects to restrain the progress of ALD. Based on proteomic analysis and enzyme-linked immunosorbent assay, ACT had been confirmed to regulate the levels of lipid biogeneration-related factors and depressed the over-accumulation of hepatic reactive oxygen species. According to further data, ACT prevented alcoholic liver injury may be associated with mediating lipid metabolism-related to PGC-1α and NF-κB signaling. In summary, ACT protected the body against chronic alcohol ingest induced liver injury through its regulation lipid on metabolism.

Background Nocturia is widely prevalent condition with detrimental effects on quality of life and general health. In Malaysia, there is a lack of up-to-date prevalence study on nocturia. This study aimed to investigate the prevalence of nocturia and awareness pertaining to nocturia among Malaysian adults. Methods A cross-sectional population-based study was conducted among Malaysian adults aged ≥ 18 years old. The data was collected by mixed mode self-administered questionnaire from May 2019 to September 2019. Nocturia was defined as one or more voids at night. Results There were a total of 4616 respondents with 74.5% of response rate. The overall prevalence of nocturia among Malaysian adults was found to be 57.3%. In multivariate analysis, respondents aged 31–40 (1.91 [1.52–2.40]) or > 60 years old (2.03 [1.48–2.71]), and those who presented with hypertension (2.84 [2.28–3.53]), diabetes mellitus (1.78 [1.42–2.25]), renal disease (3.58 [1.93–6.63]) or overactive bladder (1.61 [1.10–2.35]) were associated with higher prevalence of nocturia. A significantly lower disease prevalence (p p Conclusions The prevalence of nocturia among Malaysian adults is high and strongly influenced by age, sex, race and comorbidities. However, the general awareness pertaining to nocturia being a health issue remains low among Malaysians. The findings also highlighted the impact of nocturia on sleep and the need for nocturia education to better address this disease.

Liver cancer is the sixth most common cancer and the fourth leading cause of cancer deaths in the world. The most common type of liver cancers is hepatocellular carcinoma (HCC). Autophagy is the cellular digestion of harmful components by sequestering the waste products into autophagosomes followed by lysosomal degradation for the maintenance of cellular homeostasis. The impairment of autophagy is highly associated with the development and progression of HCC although autophagy may be involved in tumour-suppressing cellular events. In regards to its protecting role, autophagy also shelters the cells from anoikis- a programmed cell death in anchorage-dependent cells detached from the surrounding extracellular matrix which facilitates metastasis in HCC. Liver cancer stem cells (LCSCs) have the ability for self-renewal and differentiation and are associated with the development and progression of HCC by regulating stemness, resistance and angiogenesis. Interestingly, autophagy is also known to regulate normal stem cells by promoting cellular survival and differentiation and maintaining cellular homeostasis. In this review, we discuss the basal autophagic mechanisms and double-faceted roles of autophagy as both tumour suppressor and tumour promoter in HCC, as well as its association with and contribution to self-renewal and differentiation of LCSCs.

It has been reported that rs67085638 in long non‐coding RNAs (lncRNA)‐CCAT1 was associated with the risk of tumorigenesis. Also, CCAT1 could affect chemoresistance of cancer cells to paclitaxel (PTX) via regulating miR‐24‐3p and FSCN1 expression. In this study, we aimed to investigate the effect of rs67085638 on the expression of CCAT1/miR‐24‐3p/FSCN1 and the response of colon cancer to the treatment of PTX. 48 colon cancer patients were recruited and grouped by their genotypes of rs67085638 polymorphism as a CC group (N = 28) and a CT group (N = 20). PCR analysis, IHC assay and Western blot, TUNEL assay and flow cytometry were conducted. LncRNA‐CCAT1 and FSCN1 mRNA/protein were overexpressed, whereas miR‐24‐3p was down‐regulated in the CT‐genotyped patients and cells compared with those in the CC‐genotyped patients and cells. The survival of colon cancer cells was decreased, whereas the apoptosis of colon cancer cells was increased by PTX treatment in a dose‐dependent manner. MiR‐24‐3p was validated to target lncRNA‐CCAT1 and FSCN1 mRNA, and the overexpression of CCAT1 could reduce the expression of miR‐24‐3p although elevating the expression of FSCN1. Knockdown of lncRNA‐CCAT1 partly reversed the suppressed growth of CT‐genotyped tumours. And the knockdown of lncRNA‐CCAT1 partly reversed the dysregulation of lncRNA‐CCAT1 and FSCN1 mRNA/protein in rs67085638‐CT + NC shRNA mice. The findings of this study demonstrated that the presence of the minor allele of rs67085638 increased the expression of CCAT1 and accordingly enhanced the resistance to PTX. Down‐regulation of CCAT1 significantly re‐stored the sensitivity to PTX of colon cancer cells.

AIM The aim was to evaluate the physiological variation in rectoanal inhibitory reflex (RAIR) after laparoscopic intersphincteric resection (Lap-ISR) for ultralow rectal cancer. METHOD This was a retrospective study that included 56 patients who underwent Lap-ISR from a prospectively collected database. The RAIR was examined preoperatively and up to 12 months after ileostomy closure. The primary outcome included physiological variation in RAIR and its difference between partial, subtotal and total ISR. The secondary outcome was its correlation with functional outcome. RESULTS The reflex was present in 95% (53/56) of patients preoperatively, in 36% (20/56) before ileostomy closure, in 48% (27/56) at 3-6 months and in 61% (34/56) at 12 months after ileostomy closure. The elicited volume of RAIR was significantly increased at 12 months after ileostomy closure than at baseline (P = 0.005), but its duration and amplitude did not differ significantly. There was no significant difference in the reflex recovery between the ISR groups (partial vs. subtotal vs. total: 65% vs. 63% vs. 44%, P = 0.61). At 12 months after ileostomy closure, the RAIR-present group had favourable functional results and patient satisfaction (P

INTRODUCTION: Women are at higher risk of venous thromboembolism (VTE) during pregnancy and the puerperium. Global coagulation assays (GCAs), including thromboelastography (TEG), thrombin generation using the calibrated automated thrombogram (CAT) and fibrin generation using the overall haemostatic potential assay (OHP), provide a more comprehensive assessment of the coagulation process than conventional coagulation assays. We aimed to evaluate the ability of these GCAs to analyse the coagulability among pregnant women of varying VTE risk profile. METHODS: Women undergoing term elective caesarean delivery provided a single predelivery blood sample for conventional and novel coagulation testing (TEG, CAT and OHP). Data from 47 healthy nonpregnant women aged 18-45 years were used as controls. RESULTS: Sixty women with term singleton pregnancies were included. Samples from pregnant women were hypercoagulable on most GCA parameters compared to nonpregnant controls, demonstrating increased maximum amplitude (clot strength) (71.5 vs 60.6 mm, P

Although IKK-β has previously been shown as a negative regulator of IL-1β secretion in mice, this role has not been proven in humans. Genetic studies of NF-κB signaling in humans with inherited diseases of the immune system have not demonstrated the relevance of the NF-κB pathway in suppressing IL-1β expression. Here, we report an infant with a clinical pathology comprising neutrophil-mediated autoinflammation and recurrent bacterial infections. Whole-exome sequencing revealed a de novo heterozygous missense mutation of NFKBIA, resulting in a L34P IκBα variant that severely repressed NF-κB activation and downstream cytokine production. Paradoxically, IL-1β secretion was elevated in the patient’s stimulated leukocytes, in her induced pluripotent stem cell–derived macrophages, and in murine bone marrow–derived macrophages containing the L34P mutation. The patient’s hypersecretion of IL-1β correlated with activated neutrophilia and liver fibrosis with neutrophil accumulation. Hematopoietic stem cell transplantation reversed neutrophilia, restored a resting state in neutrophils, and normalized IL-1β release from stimulated leukocytes. Additional therapeutic blockade of IL-1 ameliorated liver damage, while decreasing neutrophil activation and associated IL-1β secretion. Our studies reveal a previously unrecognized role of human IκBα as an essential regulator of canonical NF-κB signaling in the prevention of neutrophil-dependent autoinflammatory diseases. These findings also highlight the therapeutic potential of IL-1 inhibitors in treating complications arising from systemic NF-κB inhibition. Refereed/Peer-reviewed

Objective To observe the clinical effect of electroacupuncture(EA) at Zhǒuling (Extra) and Ashi points in combination with blood-letting cupping for the treatment of external humeral epicondylitis (EHE). Methods Thirty EHE patients were treated with EA at Zhǒuling (Extra) and Ashi points in combination with blood-letting cupping, once every 2 days, twice a week, 4 times as one course of treatment, and 2 successive courses of treatment were given. Before treatment, after 1 course of treatment, and after 2 courses of treatment, the visual analogue scale (VAS) score and Mayo elbow performance score (MEPS) were adopted to evaluate the curative effect. Results Before treatment, the VAS score of patients was 7.81±1.39. After 1 course of treatment and after 2 courses of treatment, it was 4.77±1.56 and 2.95±1.23 respectively, lowered than before treatment, and the difference was statistically significant (both P Conclusion EA at Zhǒuling (Extra) and Ashi points and blood-letting cupping used in combination are remarkably effective in the treatment of EHE, being worthy for popularization.

Parechovirus-A (PeV-A) and Enterovirus (EV) commonly cause childhood aseptic meningitis. Bacterial meningitis in children has been associated with devastating long-term sequelae. However, developmental outcomes are unclear in Parechovirus meningitis. This study aims to review the clinical findings and developmental outcomes of infants with PeV-A and EV meningitis. We performed a retrospective study of infants aged 90 days or younger being admitted to our hospital with PeV-A meningitis between November 2015 and July 2017, with positive cerebrospinal fluid (CSF) PeV-A PCR and negative blood and CSF bacterial cultures. Hearing and neurodevelopmental outcomes were compared with a previous cohort of infants aged 90 days or younger with EV meningitis admitted from January 2015 to December 2015. A total of 161 infants were included in our study, of which 68 infants (42.2%) had PeV-A meningitis and 93 infants (57.8%) had EV meningitis. We assessed their developmental outcome at 6 months, 1 year, and 2 years post-meningitis. At 2 years post-meningitis, three infants with PeV-A meningitis had developmental delay (5.5%), whereas none with EV meningitis had developmental delay. One patient had speech delay and autism spectrum disorder, while two had mild speech delay. When compared with our cohort of EV meningitis ≤90 days old, children with PeV-A meningitis ≤90 days old were more likely to have developmental delay 2 years post-meningitis (odds ratio 2.4, 95% confidence interval 2.0–3.0, p = 0.043). None of the patients with PeV-A or EV meningitis had sensorineural hearing loss or neurological sequelae, such as cortical blindness, oropharyngeal dysphagia, hydrocephalus, epilepsy, or cerebral palsy. Infants with PeV-A meningitis had a significant risk of developmental delay 2 years post-meningitis compared with those with EV meningitis. It is important to follow-up the developmental milestones of infants diagnosed with PeV-A meningitis for at least 2 years; and when they develop developmental delay, to ensure that they receive appropriate intervention.

Objective Existing evidence on the association between vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) and cancer is limited and contradictory. No observational studies have been conducted to simultaneously address the cancer safety of VKAs and DOACs. The objective of this study was to determine whether use of VKAs and DOACs, separately, when compared with nonuse, is associated with cancer overall and prespecified site-specific incidence. Methods Using the United Kingdom Clinical Practice Research Datalink, we identified patients newly diagnosed with nonvalvular atrial fibrillation (NVAF) between 2011 and 2017. Using a time-varying exposure definition, each person-day of follow-up was classified as use of (1) VKAs, (2) DOACs, (3) VKAs and DOACs (drug switchers), and (4) nonuse of anticoagulants (reference). We also conducted a head-to-head comparison of new users of DOACs versus VKAs using propensity score fine stratification weighting. Hazard ratios (HRs) with 95% confidence intervals (CIs) for cancer overall and prespecified subtypes were estimated using Cox proportional hazards models. Results Compared with nonuse, use of VKAs was not associated with cancer overall (HR: 1.05, 95% CI: 0.91–1.22) or cancer subtypes. Similarly, use of DOACs was not associated with cancer overall (HR: 1.13, 95% CI: 0.93–1.37), but an association was observed for colorectal cancer (HR: 1.73, 95% CI: 1.01–2.99), and pancreatic cancer generated an elevated, though nonsignificant HR (HR: 2.15, 95% CI: 0.72–6.44). Results were consistent in the head-to-head comparison. Conclusion Use of oral anticoagulants is not associated with the incidence of cancer overall among patients with NVAF. Possible associations between DOACs and colorectal and pancreatic cancer warrant further study.

Heightened sympathetic nerve activity has been associated with poorer prognosis in patients with reduced left ventricular systolic function (ie, heart failure with reduced ejection fraction [HFrEF]).The purpose of this study was to investigate the effects of cardiac resynchronization therapy (CRT) on sympathetic nerve activity, measured by average skin sympathetic nerve activity (aSKNA).This prospective study enrolled 36 patients with HFrEF who received CRT. Ten patients who received an implantable cardioverter-defibrillator for primary prevention served as controls. Patient clinical data, echocardiographic variables, and aSKNA at baseline and 3-month follow-up were collected.CRT patients who exhibited wider QRS duration had higher aSKNA (1.52 ± 0.65 μV vs 0.97 ± 0.49 μV; P = .027) compared to the control group at baseline. In the CRT group, patients with QRS duration ≥150 ms had higher aSKNA than those with QRS duration150 ms (1.67 ± 0.63 μV vs 1.19 ± 0.51 μV; P =.039). After CRT, left ventricular ejection fraction (LVEF) improved from 29.6% to 35.4% (P = .001). aSKNA decreased significantly (1.52 ± 0.65 μV vs 1.31 ± 0.63 μV; P = .018). Seventeen of the 36 CRT patients were CRT responders, with LVEF improvement ≥5% at 3-month follow-up. aSKNA significantly decreased from 1.47 to 1.15 μV (P = .003) in CRT responders but was unchanged in nonresponders (1.44 ± 0.69 to 1.37 ± 0.70; P = .61). After CRT, a significant reduction in aSKNA was associated with improvement in LVEF (r = 0.638; P = .001).CRT reduces elevated sympathetic activity in HFrEF patients, accompanied by improvement in systolic function at short-term follow-up. The reduction of sympathetic activity is mainly seen in CRT responders.

Atherosclerosis is the pathological basis of most cardiovascular diseases, the leading cause of morbidity and mortality worldwide. Kallistatin, originally discovered in human serum, is a tissue-kallikrein-binding protein and a unique serine proteinase inhibitor. Upon binding to its receptor integrin β3, lipoprotein receptor-related protein 6, nucleolin, or Krüppel-like factor 4, kallistatin can modulate various signaling pathways and affect multiple biological processes, including angiogenesis, inflammatory response, oxidative stress, and tumor growth. Circulating kallistatin levels are significantly decreased in patients with coronary artery disease and show an inverse correlation with its severity. Importantly, both in vitro and in vivo experiments have demonstrated that kallistatin reduces atherosclerosis by inhibiting vascular inflammation, antagonizing endothelial dysfunction, and improving lipid metabolism. Thus, kallistatin may be a novel biomarker and a promising therapeutic target for atherosclerosis-related diseases. In this review, we focus on the antiatherogenic function of kallistatin and its potential mechanism.

Aim To assess whether dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists are associated with an increased lung cancer risk among individuals with type 2 diabetes. Methods We conducted a population-based cohort study using the UK Clinical Practice Research Datalink. We identified 130 340 individuals newly treated with antidiabetes drugs between January 2007 and March 2017, with follow-up until March 2018. We used a time-varying approach to model use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists compared with use of other second- or third-line antidiabetes drugs. We used Cox proportional hazards models to estimate the adjusted hazard ratios, with 95% CIs, of incident lung cancer associated with use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, separately, by cumulative duration of use, and by time since initiation. Results A total of 790 individuals were newly diagnosed with lung cancer (median follow-up 4.6 years, incidence rate 1.5/1000 person-years, 95% CI 1.4-1.6). Compared with use of second-/third-line drugs, use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists was not associated with an increased lung cancer risk (hazard ratio 1.07, 95% CI 0.87-1.32, and hazard ratio 1.02, 95% CI 0.68-1.54, respectively). There was no evidence of duration-response relationships. Conclusions In individuals with type 2 diabetes, use of incretin-based drugs was not associated with increased lung cancer risk.

Background Esophageal squamous cell carcinoma (ESCC) is one of the prevalent and deadly cancers worldwide. Previous studies confirmed that endothelin-1 (ET-1) serves as an oncogene and therapeutic target in various tumors. However, the role and mechanism of ET-1 in the progression of ESCC remains largely unclear. Methods Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the mRNA level of ET-1 in ESCC tissues and cell lines. Cell counting kit-8 (CCK-8), flow cytometry and Transwell assay were performed to examine the proliferation, cell cycle arrest, invasion and migration capacity of ESCC cells. Western blot was applied to measure the expression of ET-1 and PI3K/Akt pathway-related proteins. Furthermore, we also assessed the effect of ET-1 on tumor growth in vivo. Results ET-1 was highly expressed in ESCC tissues and associated with poor outcomes. Knockdown of ET-1 significantly inhibited the proliferation, migration and invasion capacity of ESCC cells and promoted cell cycle arrest. Mechanistically, silencing of ET-1 exerts anti-proliferation and anti-metastasis activities via inactivation of the PI3K/Akt signaling pathway in ESCC in vitro and in vivo. Conclusions These findings uncover the effective suppression of cell proliferation and metastasis through silencing of ET-1 and blocking the PI3K/Akt signaling pathway, which is an attractive therapeutic regimen for the treatment of ESCC.

Systemic Lupus Erythematosus (SLE) is a complex and heterogenous autoimmune disease, where genetics, immunology, and environmental factors all play a role. Murine models have contributed critical information on mechanisms of disease and prospective therapeutics. The key features that have been used to study the disease include the development of anti-nuclear autoantibodies (ANAs), splenomegaly, and kidney disease. The loss of tolerance and subsequent autoimmune features, and the progression to severe disease, are all dependent on immune dysregulation. In this article, we will describe the methods used to evaluate the underlying immunological features of the disease, as a more sensitive strategy to understand the disease itself and the mechanisms of potential novel therapeutics. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: End study protocols for tissue harvesting Basic Protocol 2: End study protocols for tissue processing Basic Protocol 3: Immunophenotyping using flow cytometry protocols Support Protocol: Tissue processing for cold storage Basic Protocol 4: Additional tissue processing for later analyses Basic Protocol 5: Analysis of serum auto-antibodies by ELISAs (ANAs, snRNP, and dsDNA).

Background: Response rates for cardiac resynchronization therapy (CRT) in patients without intrinsic left bundle-branch block (LBBB) morphology are poor.Objective: We sought to develop a nomogram model to predict response to CRT in patients without intrinsic LBBB.Methods: We searched electronic health records for patients without intrinsic LBBB who underwent CRT at Mayo Clinic. Logistic regression and Cox proportional hazards regression analysis were performed for the odds of response to CRT and risk of death, respectively. Results were used to develop the nomogram model.Results: 761 patients without intrinsic LBBB were identified. Six months after CRT, 47.8% of patients demonstrated improvement of left ventricular ejection fraction by more than 5%. The 1-, 3-, and 5-year survival rates were 95.9, 82.4, and 66.70%, respectively. Patients with CRT upgrade from pacemaker [odds ratio (OR), 1.67 (95% CI, 1.05–2.66)] or atrioventricular node (AVN) ablation [OR, 1.69 (95% CI, 1.09–2.64)] had a greater odds of CRT response than those patients who had new implant, or who did not undergo AVN ablation. Patients with right bundle-branch block had a low response rate (39.2%). Patients undergoing AVN ablation had a lower mortality rate than those without ablation [hazard ratio, 0.65 (95% CI, 0.46–0.91)]. Eight clinical variables were automatically selected to build a nomogram model and predict CRT response. The model had an area under the receiver operating characteristic curve of 0.71 (95% CI, 0.63–0.78).Conclusions: Among patients without intrinsic LBBB undergoing CRT, upgrade from pacemaker and AVN ablation were favorable factors in achieving CRT response and better long-term outcomes.

Introduction There are conflicting reports on the effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) on acute pancreatitis incidence. Objective The aim was to determine whether use of ACE inhibitors and ARBs is associated with the incidence of acute pancreatitis, compared with use of dihydropyridine calcium channel blockers (dCCBs). Methods We assembled two population-based, new-user, active comparator cohorts using the United Kingdom Clinical Practice Research Datalink linked to the Hospital Episode Statistics repository and Office for National Statistics from 1998 to 2018, with follow-up until 2019. The first cohort included 304,083 ACE inhibitor initiators and 194,431 dCCB initiators. The second cohort included 29,160 ARB initiators and 203,610 dCCB initiators. Cox proportional hazards models were fit to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of acute pancreatitis, comparing ACE inhibitors and ARBs, separately, with dCCBs. Models were weighted using standardized mortality ratio weights generated from calendar time-specific propensity scores. Results ACE inhibitors were associated with an increased risk of acute pancreatitis, compared with dCCBs (64.3 vs 45.2 per 100,000 person-years, respectively; HR 1.45, 95% CI 1.15-1.83). The number needed to harm after 2 and 5 years of use was 2438 and 1019, respectively. In contrast, ARBs were not associated with an increased risk of acute pancreatitis, compared with dCCBs (40.1 vs 47.6 per 100,000 person-years, respectively; HR 0.88, 95% CI 0.60-1.31). Conclusions ACE inhibitors were associated with a modest increased risk of acute pancreatitis compared with dCCBs. This association should be balanced with the known clinical benefits of ACE inhibitors in hypertension management. In contrast, no association was observed with ARBs.

The association between long-acting insulin analogs and colorectal cancer is uncertain, with previous studies reporting discrepant findings. To determine whether the use of long-acting insulin analogs is associated with an increased risk of colorectal cancer, when compared with use of intermediate-acting human insulins among patients with type 2 diabetes. We conducted a population-based study using the United Kingdom Clinical Practice Research Datalink (CPRD). We identified patients newly treated with either a long-acting insulin analog or an intermediate-acting human insulin between September 1, 2002 and January 31, 2018, with follow-up until January 31, 2019. Each long-acting insulin analog user was propensity score-matched to one intermediate-acting human insulin user, and a lag of 1 year was imposed. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of colorectal cancer, comparing long-acting insulin analogs with intermediate-acting human insulin. Secondary analysis was conducted to assess whether there was a duration–response relationship. A total of 10,734 new long-acting insulin analog users were matched to 10,734 new intermediate-acting human insulin users. After a median follow-up of 2.8 years, the use of long-acting insulin analogs was not associated with an increased risk of colorectal cancer, compared with intermediate-acting human insulin (1.80 vs. 1.87 per 1000 person-years, respectively; HR 0.96, 95% CI 0.70–1.34). There was no evidence of a duration–response relationship. The results of this population-based study indicate that use of long-acting insulin analogs is not associated with an overall increased risk of colorectal cancer.

Multidrug resistance (MDR) is one of the key barriers in chemotherapy, leading to the generation of insensitive cancer cells towards administered therapy. Genetic and epigenetic alterations of the cells are the consequences of MDR, resulted in drug resistivity, which reflects in impaired delivery of cytotoxic agents to the cancer site. Nanotechnology-based nanocarriers have shown immense shreds of evidence in overcoming these problems, where these promising tools handle desired dosage load of hydrophobic chemotherapeutics to facilitate designing of safe, controlled and effective delivery to specifically at tumor microenvironment. Therefore, encapsulating drugs within the nano-architecture have shown to enhance solubility, bioavailability, drug targeting, where co-administered P-gp inhibitors have additionally combat against developed MDR. Moreover, recent advancement in the stimuli-sensitive delivery of nanocarriers facilitates a tumor-targeted release of the chemotherapeutics to reduce the associated toxicities of chemotherapeutic agents in normal cells. The present article is focused on MDR development strategies in the cancer cell and different nanocarrier-based approaches in circumventing this hurdle to establish an effective therapy against deadliest cancer disease.

Aims Sulfonylureas are recommended as second-line treatment in the management of type 2 diabetes. However, they are still commonly used also as first-line treatment instead of metformin. Given the controversial cardiovascular safety of sulfonylureas, we aimed to determine if their use as first-line treatment is associated with adverse cardiovascular events among patients with newly treated type 2 diabetes compared with metformin. Methods We conducted a population-based cohort study of patients with newly treated type 2 diabetes using the UK's Clinical Practice Research Datalink. Initiators of metformin and sulfonylurea monotherapy were matched on high-dimensional propensity score, and Cox proportional hazards models were used to compare the rate of cardiovascular events (myocardial infarction, ischaemic stroke, cardiovascular death, and all-cause mortality) with sulfonylureas vs metformin. Results Our cohort included 94 750 patients initiating treatment for type 2 diabetes, 17 612 on a sulfonylurea and 77 138 on metformin. After matching, sulfonylurea monotherapy, compared with metformin monotherapy, was not associated with an increased risk of myocardial infarction (hazard ratio [HR]: 1.04, 95% confidence interval [CI]: 0.85-1.25) but was associated with increased risks of ischaemic stroke (HR: 1.25, 95% CI: 1.002-1.56), cardiovascular death (HR: 1.25, 95% CI: 1.06-1.47), and all-cause mortality (HR: 1.60, 95% CI: 1.45-1.76). This represents an additional 2.0 ischaemic strokes, 3.5 cardiovascular deaths, and 21.4 all-cause deaths per 1,000 patients per year with sulfonylureas. Conclusions Initiating treatment of type 2 diabetes with a sulfonylurea rather than metformin is associated with higher rates of ischaemic stroke, cardiovascular death, and all-cause mortality.

Normal haemostasis requires maintenance of a careful equilibrium between the necessity to clot when bleeding and the retention of fluid phase at all other times. Disruption of this equilibrium can result in catastrophic outcomes, e.g. acute myocardial infarction and pulmonary embolism. However, despite the significant therapeutic advances in cardiovascular medicine over recent years, our ability to provide an accurate cardiovascular risk assessment remains an unmet need. Routine coagulation testing is not a useful reflection of haemostasis and cannot be reliably used to predict bleeding and thrombosis risks. Global coagulation assays such as viscoelastic testing, thrombin and fibrin generation have been proposed as better measures of the haemostatic function. These assays, particularly viscoelastic testing, have been increasingly used to assess bleeding risks and guide blood product replacement in trauma and massive transfusion settings. However, the role of these assays in thrombosis is less well-defined but given the complexities of the coagulation system, these global coagulation assays when used in combination may provide a better assessment of cardiovascular and thrombosis risk at an individual level. Hence, we explore the role of some of the currently available global coagulation assays - the viscoelastic, thrombin generation and fibrin generation tests - and provide a review of the literature of the current evidence for these assays specifically in the field of venous thromboembolism and cardiovascular diseases.

Two recent observational studies have investigated the association between androgen deprivation therapy (ADT) and rheumatoid arthritis (RA), but generated discrepant findings and had important methodological limitations. Thus, the objective of this study was to determine whether the use of ADT is associated with an increased risk of RA in men with prostate cancer. We conducted a population-based cohort study using the United Kingdom Clinical Practice Research Datalink. The cohort included all men, at least 40 years of age, newly diagnosed with prostate cancer between 1 January 1988 and 31 March 2014, with follow-up until 30 September 2014. Exposure to ADT was treated as a time-varying variable and lagged by 1 year to account for diagnostic delays and latency. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of RA, comparing use of ADT with non-use. Secondary analyses were conducted to assess whether the association varied according to ADT type and cumulative duration of use. Finally, we conducted several sensitivity analyses to assess the robustness of our findings. The cohort included 32,302 men followed for a median of 3.3 years. During follow-up, 63 patients were newly diagnosed with RA, generating an incidence rate of 46.5/100,000 person-years. Compared with non-use, the use of ADT was not associated with an increased risk of RA (HR 0.84, 95% CI 0.49–1.45). In secondary analyses, the association did not vary according to ADT type or with cumulative duration of use (p trend = 0.53). The results remained consistent in sensitivity analyses. In this population-based study, the use of ADT was not associated with an increased risk of RA in men with prostate cancer.

OBJECTIVE There are uncertainties regarding the association between dipeptidyl peptidase 4 (DPP-4) inhibitors and bullous pemphigoid (BP), a potentially severe autoimmune skin disease. Thus, we conducted a population-based study to determine whether use of DPP-4 inhibitors, when compared with other second- to third-line antidiabetic drugs, is associated with an increased risk of BP in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Using the U.K. Clinical Practice Research Datalink, we conducted a cohort study among 168,774 patients initiating antidiabetic drugs between January 2007 and March 2018. Using time-dependent Cox proportional hazards models, we estimated adjusted hazard ratios (HRs) with 95% CIs of incident BP associated with current use of DPP-4 inhibitors, compared with current use of other second- to third-line antidiabetic drugs. We also conducted a propensity score–matched analysis to assess the impact of residual confounding. RESULTS During 711,311 person-years of follow-up, 150 patients were newly diagnosed with BP (crude incidence rate, 21.1 per 100,000 person-years). Current use of DPP-4 inhibitors was associated with an increased risk of BP (47.3 vs. 20.0 per 100,000 person-years; HR 2.21 [95% CI 1.45–3.38]). HRs gradually increased with longer durations of use, reaching a peak after 20 months (HR 3.60 [95% CI 2.11–6.16]). Similar results were obtained in the propensity score–matched analysis (HR 2.40 [95% CI 1.13–4.66]). CONCLUSIONS In this large population-based study, use of DPP-4 inhibitors was associated with an at least doubling of the risk of BP in patients with type 2 diabetes, albeit the absolute risk was low.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, has gradually emerged as a public health challenge worldwide. Morinda citrifolia (noni) has been used to treat various ailments by Pacific Islanders for centuries. In this work, noni fruit polysaccharide (NFP) was obtained by hot water extraction, and its structure was initially explored. The molecular weight of NFP was approximately 456 kDa, and its monosaccharide components predominantly consisted of Gala (58.44%), Gal (4.44%), Glu (21.13%), Rha (4.84%), and Ara (2.16%) to form galacturonic acid, rhamnogalacturonan-I, arabinogalactan, and arabinan. The protective effect of NFP on the intestinal mucosal barrier was then investigated using DSS-induced IBD model mice. Whereas DSS treatment inhibited intestinal mucosal expression and destroyed the tight junction of epithelial cells, by contrast, NFP promoted mucosal and tight junction protein (zonula occludens-1 and occludin) expression. In conclusion, NFP improved the clinical diagnosis of acute colitis in IBD mice and may present a potential source of IBD treatment.

Maca (Lepidium meyenii) has emerged as a popular functional plant food because of its medicinal properties and nutritional value. Macamides, as the exclusively active ingredients found in maca, are a unique series of non-polar, long-chain fatty acid N-benzylamides with multiple bioactivities such as antifatigue characteristics and improving reproductive health. In this study, a new kind of macamide, N-benzyl eicosapentaenamide (NB-EPA), was identified from maca. We further explore its potential neuroprotective role in hypoxic–ischemic brain injury. Our findings indicated that treatment with biosynthesized NB-EPA significantly alleviates the size of cerebral infarction and improves neurobehavioral disorders after hypoxic–ischemic brain damage in neonatal mice. NB-EPA inhibited the apoptosis of neuronal cells after ischemic challenge. NB-EPA improved neuronal cell survival and proliferation through the activation of phosphorylated AKT signaling. Of note, the protective property of NB-EPA against ischemic neuronal damage was dependent on suppression of the p53–PUMA pathway. Taken together, these findings suggest that NB-EPA may represent a new neuroprotectant for newborns with hypoxic–ischemic encephalopathy.

Macamides are a class of bioactive amide alkaloids found only in maca (Lepidium meyenii). Recent studies have shown that macamide-rich extracts possess various biological activities, such as antioxidative, immune-enhancing, and reproductive health-improving activities. In the present study, N-benzyl docosahexaenamide (NB-DHA), a newly identified macamide with the highest degree of unsaturation among all identified macamides, was identified from the maca extract. Microalgae oil, a docosahexaenoic acid-rich substance, was used as the starting material for the synthesis of NB-DHA. The effects of NB-DHA in colitis-induced mice were evaluated. NB-DHA significantly alleviated weight loss, shortening of colon length, and occult blood occurrence in mice with dextran sulfate sodium-induced colitis. Histological analysis revealed that following the administration of NB-DHA in mice with colitis, the infiltration of inflammatory cells and levels of proinflammatory factors, such as tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and myeloperoxidase, decreased, whereas the level of the anti-inflammatory factor IL-10 increased. Furthermore, the decreased expression of intestinal tight junction proteins caused by colitis was upregulated by the administration of NB-DHA. These results indicate that NB-DHA could be developed as a therapeutic agent for ulcerative colitis.

Objectives To investigate a strategy for ultra-low volume contrast percutaneous coronary intervention (PCI) with the aims of preserving renal function and observing the 90-day clinical endpoint in patients with non-ST-elevated myocardial infarction (non-STEMI) and chronic kidney disease (CKD). Background The feasibility, safety, and clinical utility of PCI with ultra-low radio-contrast medium in patients with non-STEMI and CKD are unknown. Methods A total of 29 patients with non-STEMI and CKD (estimated glomerular filtration rate [eGFR] of ≤60 ml/min/1.73 m2 ) were included. Ultra-low volume contrast PCI was performed after minimal contrast coronary angiography using zero contrast optical coherence tomography (OCT) guidance. Pre- and post-PCI angiographic measurements were performed using quantitative flow ratio (QFR) for pre-perfusion assessment and verifying improvement. Results The median creatinine level was 2.1 (inter-quartile range 1.8-3.3), and mean eGFR was 48 ± 8 ml/min/1.73 m2 pre-PCI. During the PCI procedure, OCT revealed 15 (52%) cases of abnormalities post-dilation. There was no significant change in the creatinine level and eGFR in the short- or long-term, and no major adverse events were observed. Conclusion In non-STEMI patients with high-risk CKD who require revascularization, QFR and no contrast OCT-guided ultra-low contrast PCI may be performed safely without major adverse events.

Death-associated protein kinase (DAPK) is a Ca2+/CaM-regulated protein kinase that is involved in cell death processes by multiple pathways. It has been reported that DAPK may play a role in brain ischemia-induced neuronal death, but this mechanism is not well understood. DANGER, a membrane-associated protein that binds to DAPK physiologically, inhibits DAPK activation. In the present study, we used a transient global brain ischemia and reperfusion (I/R) rat model to investigate whether the interaction between DAPK and DANGER is involved in neuronal cell death following brain ischemia, and to reveal the mechanism of action. Our results indicate that the DAPK/DANGER interaction in the hippocampal CA1 region was significantly reduced after I/R with a peak reduction at 6 h. We further demonstrate that the NMDA inhibitor MK-801, DAPK inhibitor, or calcineurin inhibitor FK-506 prevented the dissociation of DANGER from DAPK 6 h after I/R. This was accompanied by a significantly decreased I/R-induced dephosphorylation of DAPK(ser-308), inhibiting DAPK catalytic activity. Moreover, the expression of DANGER and the interaction between DANGER and IP3R on the endoplasmic reticulum was significantly increased at I/R 6 h, which may be related to a reduction of DAPK/DANGER binding under I/R condition. Furthermore, MK-801, DAPK inhibitor and FK-506 had neuroprotective effects against hippocampal CA1 neuronal death 5 days after I/R. In conclusion, our data suggest that the dissociation of DANGER from DAPK may mediate DAPK activation, which is involved in DAPK-related neuronal death following I/R injury.

Introduction: There are concerns that hydrochlorothiazide may increase the risk of incident nonmelanoma (cutaneous squamous cell carcinoma [cSCC], basal cell carcinoma [BCC]) and melanoma skin cancer, with regulatory agencies and societies calling for additional studies. Methods: We conducted a propensity score-matched population-based cohort study using the United Kingdom Clinical Practice Research Datalink. A total of 20,513 new users of hydrochlorothiazide were propensity score matched, in a 1:1 ratio, to new users of other thiazide diuretics between January 1, 1988 and March 31, 2018, with follow-up until March 31, 2019. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for cSCC, BCC, and melanoma, comparing use of hydrochlorothiazide with use of other thiazide diuretics overall, by cumulative duration of use, and cumulative dose. Results: After an 8.6-year median follow-up, hydrochlorothiazide was associated with an increased risk of cSCC (HR 1.50, 95% CI 1.06–2.11). HRs increased with cumulative duration of use, with evidence of an association after 5–10 years (HR 2.10, 95% CI 1.20–3.67) and highest after > 10 years (HR 3.70, 95% CI 1.77–7.73). Similarly, HRs increased with cumulative dose, with higher estimates for ≥ 100,000 mg (HR 4.96, 95% CI 2.51–9.81). In contrast, hydrochlorothiazide was not associated with an increased risk of BCC (HR 1.01, 95% CI 0.91–1.13) or melanoma (HR 0.82, 95% CI 0.63–1.08), with no evidence of duration– or dose–response relationships. Conclusions: Use of hydrochlorothiazide was associated with an increased risk of cSCC and with evidence of a duration– and dose–response relationship. In contrast, no association was observed for BCC or melanoma.

We aim to determine the correlation between parental rearing, personality traits, and obsessive–compulsive disorder (OCD) in different quantiles. In particular, we created an intermediary effect model in which parental rearing affects OCD through personality traits. All predictors were measured at the time of the survey, comprising parental rearing (paternal rearing and maternal rearing), demographics (grade and gender), and personality traits (neuroticism, extroversion, and psychoticism). These results suggest that (a) paternal emotional warmth was negatively correlated with OCD at the 0.40–0.80 quantile, while maternal emotional warmth was positively correlated with the OCD at the 0.45–0.69 quantile. (b) The correlation between negative parental rearing and OCD ranged from the 0.67 to 0.95 quantile for paternal punishment, 0.14–0.82 quantile for paternal overprotection, 0.05–0.36 and >0.50 quantile for maternal over-intervention and overprotection, and 0.08–0.88 quantile for maternal rejection. (c) Extroversion, neuroticism, and psychoticism were not only associated with OCD in a particular quantile but also mediated between parental rearing (namely parental emotional warmth, paternal punishment, paternal overprotection, maternal rejection, maternal over-intervention, and overprotection) and OCD. These findings provide targets for early interventions of OCD to improve the form of family education and personality traits and warrant validation.

The United States Food and Drug Administration is considering replacing cardiovascular outcome trials (CVOTs) of antidiabetic drugs with trials that better represent patients with type 2 diabetes. However, designing such representative trials requires understanding the underlying target populations (i.e., populations intended to receive the drug in the real-world setting). Thus, we used the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial as a motivating example to illustrate how different target populations impact trial representativeness. Using the United Kingdom Clinical Practice Research Datalink, we identified three target populations: 1) all patients with type 2 diabetes; 2) patients prescribed liraglutide; 3) patients who would have been eligible to receive liraglutide based on treatment stage (i.e., patients with poorly controlled diabetes eligible to receive a second-to-fifth line antidiabetic drug). We then examined the representativeness of the LEADER trial by applying its eligibility criteria to each target population. The target populations of patients with type 2 diabetes (n=279,763), those prescribed liraglutide (n=14,421), and those eligible to receive liraglutide based on the treatment stage (n=85,610) differed substantially in terms of hemoglobin A1c, body mass index, prevalence of heart failure, and chronic kidney disease. Applying the LEADER trial eligibility criteria to these target populations resulted in the inclusion of 19.1%, 20.7%, and 34.8% patients, respectively. This study highlights how real-world data can be used to define different target populations. Explicitly defining these target populations can help in the design of future trials of antidiabetic drugs.

External controls have been primarily used in the setting of single-arm trials of rare diseases; their use in common diseases has not been readily investigated, nor is there guidance on how to best select comparators. Thus, the objective of this study was to emulate a large cardiovascular outcome trial of type 2 diabetes to compare associations of effectiveness with different comparator groups to those reported in the trial. Using the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, we investigated six comparator groups using three calendar time periods (Early: 1999-2003; Later: 2004-2008, and Contemporaneous: 2009-2013) and two comparators (sulfonylureas and other second-to-third-line antidiabetic drugs). Hazard ratios (HRs) of the three-point composite cardiovascular outcome were estimated using four variations of the propensity score (adjustment, stratification, fine stratification, and matching) and compared with the LEADER trial (HR, 0.87; 95% confidence interval, 0.78-0.97). When comparing users of liraglutide with users of sulfonylureas, the HRs ranged from 0.57 to 1.03, with estimates in the early period most closely reflecting the LEADER trial (HR, 0.57-0.88). In contrast, the HRs ranged from 0.73 to 0.97 when comparing liraglutide users with users of any second-to-third-line antidiabetic drugs, although the later period generated estimates closest to the LEADER trial (HR, 0.77-0.84). Different methods of adjustment led to generally consistent HRs, aside from the fine stratification in the early period. This study highlights the complex interplay between comparator, temporality, and method of adjustment when selecting comparators using real-word data. These design choices must be considered in the design of trial emulation studies.

Objectives To identify and quantify the level of CD34+CD133+CD309+ circulating angiogenic cells (CAC) and explore factors associated with the level of CAC in patients with SLE. Methods The peripheral blood mononuclear cells of consecutive SLE patients and demographically matched healthy controls (HC) were extracted and identified, enumerated and compared for CAC levels by multi-colour flow cytometry based on the EULAR Scleroderma Trials and Research (EUSTAR) recommendation. Meta-analyses were performed by combining the current and previous case–control studies, aiming to increase the statistical power to discern the difference in CAC level between SLE patients and HC. Mixed-model meta-regression was conducted to explore potential demographic and clinical factors that were associated with CAC level. Results A lower level of CAC was found in 29 SLE patients compared with 24 HC [mean (s.d.) 10.76 (13.9) vs 24.58 (25.4) cells/ml, P = 0.015]. Random-effects meta-analyses of the current and six previously published case–control studies involving 401 SLE patients and 228 HC revealed a lower CAC level compared with HC (standardized mean difference = –2.439, P = 0.001). Meta-regression analysis demonstrated that HCQ use was associated with a more discrepant CAC level between both groups (P = 0.01115). Conclusion SLE patients had a significantly lower CD34+CD133+CD309+ CAC level than HC, and HCQ use was associated with a more discrepant CAC level between SLE patients and HC. This study triggers further observational, interventional and mechanistic studies to address the beneficial impact of HCQ on the functionality of CAC in SLE patients.

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are second- to third-line antidiabetes drugs that have been shown to have cardiovascular benefits. However, in premarketing trials of the SGLT2 inhibitor dapagliflozin, there were numerical imbalances in breast cancer events compared with placebo; all occurred within 1 year of randomization (rate ratio 2.47, 95% CI 0.64–14.10) (1). In contrast, no imbalances were observed in subsequent large cardiovascular outcome trials of dapagliflozin and other SGLT2 inhibitors (2–4). While the discrepant findings between the pre- and postmarketing trials could be due to chance, one hypothesis is that the early breast cancer imbalances are the result of an accelerated tumor-promoting effect of SGLT2 inhibitors. However, this is unlikely, given that sodium–glucose cotransporter proteins are not expressed in mammary tissue, and animal studies have failed to demonstrate that SGLT2 inhibitors have any neoplastic activity (5). Another hypothesis relates to the weight-lowering effects of SGLT2 inhibitors, which could facilitate the detection of existing breast lumps, thus leading to a transient overdetection of breast cancer. To date, this possible association has not been investigated in the real-world setting. We conducted a population-based cohort study using the U.K. Clinical Practice Research Datalink (CPRD) (protocol: 19_272). We identified all female patients newly treated with either an SGLT2 inhibitor (dapagliflozin, …

Metaplastic breast carcinoma (MBC) is a highly aggressive form of triple-negative cancer (TNBC), defined by the presence of metaplastic components of spindle, squamous, or sarcomatoid histology. The protein profiles underpinning the pathological subtypes and metastatic behavior of MBC are unknown. Using multiplex quantitative tandem mass tag-based proteomics we quantify 5798 proteins in MBC, TNBC, and normal breast from 27 patients. Comparing MBC and TNBC protein profiles we show MBC-specific increases related to epithelial-to-mesenchymal transition and extracellular matrix, and reduced metabolic pathways. MBC subtypes exhibit distinct upregulated profiles, including translation and ribosomal events in spindle, inflammation- and apical junction-related proteins in squamous, and extracellular matrix proteins in sarcomatoid subtypes. Comparison of the proteomes of human spindle MBC with mouse spindle (CCN6 knockout) MBC tumors reveals a shared spindle-specific signature of 17 upregulated proteins involved in translation and 19 downregulated proteins with roles in cell metabolism. These data identify potential subtype specific MBC biomarkers and therapeutic targets., Metaplastic breast carcinoma (MBC) is among the most aggressive subtypes of triple-negative breast cancer (TNBC) but the underlying proteome profiles are unknown. Here, the authors characterize the protein signatures of human MBC tissue samples and their relationship to TNBC and normal breast tissue.

Background: It has been proposed that the weight loss associated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may improve the detection of breast cancer in patients undergoing this treatment. Thus, this study aimed to determine whether the weight-lowering effects of GLP-1 RAs is associated with an increased detection of breast cancer among obese women with type 2 diabetes. Methods: Using the United Kingdom Clinical Practice Research Datalink, we conducted a propensity score-matched cohort study among female obese patients with type 2 diabetes newly-treated with antidiabetic drugs between 1 January 2007 and 31 January 2018. New users of GLP-1 RAs (n=5,510) were matched to new users of second- to third-line non-insulin antidiabetic drugs (n=5,510). Time-dependent Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer associated with different GLP-1 RA maximal weight loss categories (10%). Results: Breast cancer incidence gradually increased with GLP-1 RA maximal weight loss categories, with the highest HR observed for patients achieving at least 10% weight loss (HR: 1.77, 95% CI: 1.12, 2.81). In secondary analyses, the HR for >10% weight loss was highest in the 2-3 years since treatment initiation (HR: 2.90, 95% CI: 1.21, 6.92). Conclusions: In this population-based study, the detection of breast cancer gradually increased with GLP-1 RA weight loss categories, particularly among those achieving >10% weight loss. These results suggest that significant weight loss with GLP-1 RAs may improve the detection of breast cancer among obese patients with type 2 diabetes.

Background The purpose of our study was to explore the relationship between body weight and short- and long-term clinical outcomes in patients with sepsis. Methods We retrospectively analyzed 11,499 patients with sepsis at the Beth Israel Deaconess Medical Center (Boston, MA, USA) registered in the Medical Information Market Intensive Care (MIMIC-III) database from 2001 to 2012. Cox proportional hazards regression assessed the relationships between body mass index and 30-day and 1-year mortality. Results Patients were divided into four groups according to body mass index (underweight: 336 [6.0%]; normal weight: 1,752 [31.4%]; overweight: 1,563 [28.1%]; and obese: 1,920 [34.5%]), 30-day mortality (42.3%, 36.6%, 32.2%, and 29.6%; p

OBJECTIVE Previous studies suggested that glucagon-like peptide 1 receptor agonists (GLP-1 RAs) may initially worsen and possibly increase the risk of diabetic retinopathy. However, data on this possible association remain limited. Thus, this population-based study aimed to determine whether use of GLP-1 RAs is associated with an increased risk of incident diabetic retinopathy. RESEARCH DESIGN AND METHODS Using the U.K. Clinical Practice Research Datalink (CPRD), we conducted a cohort study among 77,115 patients with type 2 diabetes initiating antidiabetic drugs between January 2007 and September 2015. Adjusted hazard ratios (HRs) and 95% CIs of incident diabetic retinopathy were estimated using time-dependent Cox proportional hazards models, comparing use of GLP-1 RAs with current use of two or more oral antidiabetic drugs. In an ancillary analysis, new users of GLP-1 RAs were compared with new users of insulin. RESULTS During 245,825 person-years of follow-up, 10,763 patients were newly diagnosed with diabetic retinopathy. Compared with current use of two or more oral antidiabetic drugs, use of GLP-1 RAs was not associated with an increased risk of incident diabetic retinopathy overall (HR 1.00, 95% CI 0.85–1.17). Compared with insulin, GLP-1 RAs were associated with a decreased risk of diabetic retinopathy (HR 0.67, 95% CI 0.51–0.90). CONCLUSIONS The associations with diabetic retinopathy varied according to the type of comparator. When compared with use of two or more oral antidiabetic drugs, use of GLP-1 RAs was not associated with an increased risk of incident diabetic retinopathy. The apparent lower risk of diabetic retinopathy associated with GLP-1 RAs compared with insulin may be due to residual confounding.

This study investigated the effect of glucocorticoids combined with probiotics on inflammatory factors and intestinal microflora in the treatment of Crohn's disease. Eighty-three patients with Crohn's disease were selected from March 2015 to December 2017 in PLA Army General Hospital (Beijing, China). A total of 83 patients were randomly divided into the control group and treatment group. Patients in the control group were treated with routine treatment of oral sulfasalazine. Besides oral sulfasalazine, patients in the treatment group were treated with probiotics combined with glucocorticoids. At the same time, a total of 40 healthy individuals were selected to serve as the healthy group (received no treatment). Clinical efficacy, changes of inflammatory factors, incidence of infection and changes of intestinal flora were compared between the different groups. After treatment, the levels of inflammatory factors in both groups significantly decreased, and the reduction in the treatment group significantly increased than that in the control group (P

Myeloproliferative neoplasms (MPN) are independent risks for thrombotic events. Routine laboratory tests are inadequate to evaluate the underlying procoagulant state. Global coagulation assays such as thromboelastography, thrombin and fibrin generation may provide better assessment of coagulation activation and thereby of thrombosis risk. Participants with MPN were recruited. Thromboelastography was performed on citrated whole blood while thrombin generation using calibrated automated thrombogram, fibrin generation using overall haemostatic potential assays and P-selectin were quantified on platelet-poor plasma. Thirty-eight MPN patients (median age: 65 years) were recruited. There were 26 patients with essential thrombocythemia (68.4%), eight polycythemia vera (20.5%), three primary myelofibrosis and one MPN, unclassifiable. Compared with normal controls, there was no difference in maximum amplitude although lysis time (LY30) was significantly higher (2.9 vs. 0.6%, adjusted P < 0.01) using thromboelastography. Calibrated automated thrombogram showed higher thrombin peak (260.8 vs. 222.6 nmol/l; P < 0.01) and velocity index (91.1 vs. 65.0 nmol/l/min; P < 0.01) with comparable endogenous thrombin potential. Fibrin generation parameters were significantly reduced with preserved overall fibrinolytic potential, whereas P-selectin was markedly increased (108.9 vs. 49.3 ng/ml, P < 0.01). This study demonstrated unique differences between MPN population and normal controls using a combination of global coagulation assays. The presence of high lysis time (LY30) and reduced fibrin generation in MPN patients were contradictory to the prothrombotic nature and may represent a compensatory effort to achieve equilibrium within the Virchow's triad. Both markers may be important prognostic indicators of thrombosis in MPN and further prospective studies to confirm these findings are proposed.

Background A large trial of postmenopausal women with breast cancer reported an imbalance in colorectal cancer events with aromatase inhibitors (AIs), compared with tamoxifen in the adjuvant setting. This unexpected signal was observed within 3 years of randomization. To date, no observational studies have examined this important safety question in the natural setting of clinical practice. Thus, the objective of this study was to determine whether AIs, when compared with tamoxifen, are associated with increased risk of colorectal cancer in postmenopausal women with breast cancer. Patients and methods Using the UK Clinical Practice Research Datalink, we identified women, at least 55 years of age, with breast cancer newly treated with either AIs or tamoxifen between 1 January 1996 and 30 September 2015, with follow-up until 30 September 2016. High-dimensional propensity score-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of incident colorectal cancer associated with AIs when compared with tamoxifen overall, by cumulative duration of use, and time since initiation. All exposures were lagged by 1 year for latency considerations. Results A total of 9701 and 8893 patients initiated AIs and tamoxifen as first-line hormonal therapy (median follow-up of 2.4 and 2.9 years, respectively). Compared with tamoxifen, AIs were not associated with an increased risk of colorectal cancer (incidence rates of 150 per 100 000 person-years in both groups; adjusted HR: 0.90, 95% CI: 0.53–1.52). Similarly, there was no evidence of an association with cumulative duration of use (P-heterogeneity = 0.54), and time since initiation (P-heterogeneity = 0.66). Conclusions In this first population-based study, the use of AIs was not associated with an increased risk of colorectal cancer. These findings should provide reassurance to the concerned stakeholders.

Background Non–vitamin K antagonist oral anticoagulants (NOACs) are relatively new drugs used for stroke prevention in nonvalvular atrial fibrillation (NVAF). However, there are concerns that their use may be associated with hepatotoxic effects. Objectives The purpose of this study was to determine whether the use of NOACs is associated with an increased risk of serious liver injury compared with the use of vitamin K antagonists (VKAs) in NVAF patients with and without prior liver disease. Methods Using the administrative databases of the Canadian province of Quebec’s health insurances, the authors conducted a cohort study among patients newly diagnosed with NVAF between January 2011 and December 2014. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of serious liver injury (defined as either a hospitalization or related death) were estimated using time-dependent Cox proportional hazards models, comparing current use of NOACs to current use of VKAs separately among patients with or without prior liver disease. Results The cohort comprised 51,887 patients, including 3,778 with prior liver disease. During 68,739 person-years of follow-up, 585 patients experienced a serious liver injury. Compared with current use of VKAs, current use of NOACs was not associated with an increased risk of serious liver injury in patients without or with prior liver disease (adjusted HR: 0.99; 95% CI: 0.68 to 1.45; and adjusted HR: 0.68; 95% CI: 0.33 to 1.37, respectively). Conclusions Compared with VKAs, NOACs were not associated with an increased risk of serious liver injury irrespective of baseline liver status. Overall, these results provide reassurance regarding the hepatic safety of NOACs.