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BACKGROUND We aimed to determine risk factors for incident CKD in a large population-based cohort. METHODS This prospective opt-in population-based cohort study is based on the 45 and Up Study, where New South Wales residents aged ≥45 years were randomly sampled from the Services Australia enrolment database and agreed to complete the 45 and Up Study baseline questionnaire and have their responses linked to their health data in routinely-collected databases. The primary outcome was the development of incident CKD, defined as eGFR

Lobular capillary hemangioma (LCH) is a rapidly growing benign vascular neoplasm of unknown etiology. LCH usually occurs on the cutaneous and mucosal surfaces, such as gingiva, lips, fingers, and face. LCH was previously called ‘pyogenic granuloma (PG),’ because it was thought to be granulation of tissue occurring in reaction to an infectious etiology despite the fact that it demonstrates no infectious signs in histology or microbiology. Instead, its features seem more like angiomatous lesions rather than granulomatous lesions, so the term ‘LCH’ has been used thereafter. Reports of LCH of hypopharynx have been rare. Here we report a 63-yearold male patient with LCH of hypopharynx with a review of related literature.

The availability of direct-acting antivirals (DAAs) sparked efforts to eliminate hepatitis C virus (HCV) in Australia. We evaluated whether an educational intervention of a 1-h discussion among staff using audit and feedback data from the MedicineInsight GP programme would improve DAA uptake. Of 296 eligible general practices in MedicineInsight, 11% opted out. Randomization stratified by practice caseload allocated 130 practices to the intervention arm and 129 to control. The primary outcome was the number of patients started on DAAs over 6 months using the negative binomial regression model adjusted for DAA prescription history and clustering by practice. Data for analysis were available for 78% of practices, which included 101 practices and 2469 DAA-naive patients with confirmed/possible HCV in the intervention arm, and 100 practices and 2466 patients in the control arm. At baseline, 49.5% of practices had prescribed ≥1 DAA in the past year; 18.9% of HCV patients had already been treated with DAAs; the mean age of DAA-naive HCV patients was 43 years old, and 57% were men. Over 6 months, 43 patients in the intervention arm and 36 in the control arm started DAAs (adjusted IRR 1.19; 95% CI 0.67-2.11, p = 0.55). In the first 3 months, 27 vs 16 patients started DAAs (adjusted IRR 1.77, 0.88-3.58; p = 0.111). Few patients were started on DAAs, and a facilitated discussion in HCV management did not lead to a significant increase. Alternative measures, such as incentivizing GP initiations or patients, are suggested to address remaining barriers to DAA uptake in Australian primary care. Australian New Zealand Clinical Trial Registry (ANZCTR) Registration Number: ACTRN12619000508178p.

Severe tooth decay has been associated with iron deficiency anemia that disproportionally burdens susceptible populations. Current modalities are insufficient in severe cases where pathogenic dental biofilms rapidly accumulate, requiring new antibiofilm approaches. Here, we show that ferumoxytol, a Food and Drug Administration-approved nanoparticle formulation for treating iron deficiency, exerts an alternative therapeutic activity via the catalytic activation of hydrogen peroxide, which targets bacterial pathogens in biofilms and suppresses tooth enamel decay in an intraoral human disease model. Data reveal the potent antimicrobial specificity of ferumoxytol iron oxide nanoparticles (FerIONP) against biofilms harboring Streptococcus mutans via preferential binding that promotes bacterial killing through in situ free-radical generation. Further analysis indicates that the targeting mechanism involves interactions of FerIONP with pathogen-specific glucan-binding proteins, which have a minimal effect on commensal streptococci. In addition, we demonstrate that FerIONP can detect pathogenic biofilms on natural teeth via a facile colorimetric reaction. Our findings provide clinical evidence and the theranostic potential of catalytic nanoparticles as a targeted anti-infective nanomedicine.

There are limited data on whether estimated glomerular filtration rate (eGFR) variability modifies the risk of future clinical outcomes in type 2 diabetes (T2D). We assessed the association between 20-month eGFR variability and the risk of major clinical outcomes in T2D among 8241 participants in the ADVANCE trial. Variability in eGFR (coefficient of variation [CVeGFR ]) was calculated from three serum creatinine measurements over 20 months. Participants were classified into three groups by thirds of CVeGFR : low (≤6.4; reference), moderate (>6.4 to ≤12.1) and high (>12.1). The primary outcome was the composite of major macrovascular events, new or worsening nephropathy and all-cause mortality. Cox regression models were used to estimate hazard ratios (HRs). Over a median follow-up of 2.9 years following the 20-month period, 932 (11.3%) primary outcomes were recorded. Compared with low variability, greater 20-month eGFR variability was independently associated with higher risk of the primary outcome (HR for moderate and high variability: 1.07, 95% CI: 0.91-1.27 and 1.22, 95% CI: 1.03-1.45, respectively) with evidence of a positive linear trend (p = .015). These data indicate that eGFR variability predict changes in the risk of major clinical outcomes in T2D.

Aim To assess whether the effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors on cardiovascular, kidney and mortality outcomes are consistent with and without concomitant metformin use.Material and methods We conducted a meta-analysis of event-driven, randomized, placebo-controlled SGLT2 inhibitor trials that reported cardiovascular, kidney or mortality outcomes by baseline metformin use. Treatment effects, reported as hazards ratios (HRs) and 95% confidence intervals (CIs), were pooled using random-effects meta-analysis. The main outcomes in this analysis were (i) major adverse cardiovascular events (MACE) and (ii) hospitalization for heart failure (HHF) or cardiovascular death.Results We included six trials of four SGLT2 inhibitors that enrolled a total of 51 743 participants. Baseline metformin use varied from 21% in DAPA-HF to 82% in DECLARE-TIMI 58. SGLT2 inhibitors reduced the risk of MACE, with and without concomitant metformin use (HR 0.93, 95% CI 0.87-1.00 and HR 0.82, 95% CI 0.71-0.86, respectively; P-heterogeneity = 0.14). There were also clear and separate reductions in HHF or cardiovascular death with SGLT2 inhibitors, irrespective of metformin use (HR 0.79, 95% CI 0.73-0.86 and HR 0.74, 95% CI 0.63-0.87, respectively; P-heterogeneity = 0.48), as well as for major kidney outcomes and all-cause mortality (all P-heterogeneity > 0.40).Conclusion Treatment with SGLT2 inhibitors results in clear and consistent reductions in cardiovascular, kidney and mortality outcomes regardless of whether patients are receiving or not receiving metformin.

Background In patients with congenital melanocytic nevus (CMN), single-stage removal of large lesions can be difficult because the high tension created by excising and repairing a large lesion may result in scar widening. Herein, we introduce a method to effectively excise lesions while minimizing scarring and compare its outcomes to those of existing surgical methods. Methods We compared patients who underwent surgery using the anchoring technique (n=42) or the conventional elliptical technique (n=36). One side of the lesion was removed via en bloc resection up to the superficial fascia. The other side of the lesion was removed via de-epithelialization. The de-epithelialized dermal flap was then fixed by suturing it to the superficial fascia on the opposite side. The length of the lesion’s long axis and amount of scar widening were measured immediately after surgery and at 2, 6, and 12 months postoperatively. At 12 months, patients were assessed using the Patient and Observer Scar Assessment Scale. Results The lesion locations included the face, arms, legs, back, and abdomen. The anchoring method resulted in shorter and smaller scars than the conventional method. There were no cases of postoperative hematoma or wound dehiscence. Significant differences in postoperative scar widening were found in the arm and leg areas (P Conclusions The anchoring method introduced in this study can provide much better outcomes than the conventional method. The anchoring method is particularly useful for the removal of CMN around the joints or extremities, where the surgical site is subjected to high tension.

Background The clinical significance of lipid profile in gastric cancer remains unclear. The aim of the present study was to investigate the correlation between serum lipid profiles and patient clinical parameters as well as prognosis in gastric cancer. Methods The preoperative plasma lipid profile levels of 358 gastric cancer patients, who were operated in between 2001 and 2009, were retrospectively evaluated, and the correlation between these factors and patient clinical parameters as well as survival were analyzed. Results There was a significant association between serum high-density lipoprotein cholesterol level (HDL-C

In this systematic review and meta-analyses, we sought to determine sex-disparities in treatment abandonment in children with cancer in low- and middle-income countries (LMICs) and identify the characteristics of children and their families most disadvantaged by such abandonment. Sex-disaggregated data on treatment abandonment were collated from the available literature and a random-effects meta-analysis was conducted to compare the rates in girls with those in boys. Subgroup analyses were conducted in which studies were stratified by design, cancer type and the Gender Inequality Index of the country of study. Eighteen studies were included in the systematic review and of these studies, 16 qualified for the meta-analysis, representing 10 754 children. The pooled rate of treatment abandonment overall was 30%. We observed no difference in the proportion of treatment abandonment in girls relative to estimates observed in boys (rate ratio [RR] 0.95, 95% CI: 0.79-1.15; P = .61). There was significant heterogeneity across the included studies and in the pooled estimate of RR for girls vs boys (both I2 > 98%). Subgroup analyses did not reveal any effect on abandonment risk. Risk factors for abandonment observed fell into three main categories: socio-demographic; geographic; and travel-related. In conclusion, a high rate of treatment abandonment (30%) was observed overall for children with cancer in included studies in LMICs, although this was variable and context specific. No evidence of gender bias in childhood cancer treatment abandonment rates across LMICs was found. Given that the risk factors for abandonment are context specific, in-depth country-level analyses may provide further insights into the role of a child's gender in treatment abandonment decisions.

Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most prevalent inborn disorder. This X-chromosome-linked recessive disease affects more than 400 million people globally, and is associated with haemolytic anaemia after medication with the anti-latent malaria drug, primaquine. To prevent malaria, the Republic of Korea (ROK) Army administers malaria chemoprophylaxis. Due to the previously low G6PD deficiency prevalence in the ROK, prior to primaquine administration, testing for G6PD deficiency was not mandatory. In this study, to evaluate the risk from malaria chemoprophylaxis in the ROK, G6PD deficiency prevalence was investigated. Methods Blood specimens from 1632 soldiers entering training camp for the 3rd Infantry of the ROK Army were collected. CareStart™ Biosensor for G6PD and haemoglobin (Hb) was used to detect G6PD levels. G6PD variants using the DiaPlexC G6PD Genotyping kit (Asian type) and full-length sequencing were examined. Results Of 1632 blood specimens tested, none was observed to be G6PD deficient. The median value of all tested samples was 7.582 U/g Hb. An investigation of 170 G6PD DNA variants was analysed and categorized as partially low normal [n = 131, 30–80% (2.27–6.05 U/g Hb) of the median value], high [n = 3, > 150% (> 11.373 U/g Hb) of the median value], or normal [n = 36, 80–150% (6.05–11.373 U/g Hb) of the median value], and none was amplified by the DiaPlexC kit. Five silent mutations (C→T) in 131 partially low normal specimens were found at the 1311th nucleotide position by sequence analysis. Another 8 silent mutations (T93C) were also detected in 131 partially low normal specimens. Thus, it is inferred that these silent mutations could be related to G6PD activity. Conclusions This G6PD deficiency prevalence study, conducted among participants from the 3rd Infantry of the ROK Army, provided crucial evidence for the safety of malaria chemoprophylaxis. This study showed that the prevalence of G6PD deficiency among 1632 young soldiers was wholly absent. Although G6PD phenotypic mutations were not detected, many silent mutations (C1311T and T93C) were observed. Thus, it is inferred that malaria chemoprophylaxis is relatively safe against G6PD deficiency-mediated haemolytic anaemia. However, given the number of individuals whose G6PD were at the partially low normal range and the frequent detection of G6PD deficiency-related mutations, consistent monitoring of G6PD deficiency is needed.

Background Creatinine-based estimated glomerular filtration rate (eGFR) is biased in the setting of obesity and other conditions. Alternative kidney filtration markers may be useful in adults with diabetes, but few studies examined the associations with risk of clinical outcomes. Methods In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, we evaluated whether baseline levels and change in eGFR based on creatinine (Cr), cystatin c (Cys), β2 -microglobulin (B2M), eGFRCr-Cys , and the average of three estimates (eGFRCr-Cys-B2M ) assessed in 7217 participants at baseline and a random sample of 640 participants at the 1 year visit are associated with clinical outcomes. We examined associations with major macrovascular and microvascular events together and separately, and all-cause mortality using Cox regression models, adjusting for established risk factors. Results Over a median follow-up of 5 years, 1313 major macrovascular (n = 748) and microvascular events (n = 637), and 743 deaths occurred. Lower levels of eGFR based on all filtration markers individually and combined were associated with 1.4 to 3.0 times higher risk of major macrovascular and microvascular events (combined and separately) and all-cause mortality. Per 30% decline in eGFRCys , eGFR Cr-Cys , and eGFRCr-Cys-B2M were associated with a > 2-fold higher risk of all clinical outcomes. Conclusions In adults with type 2 diabetes, baseline levels of eGFR based on alternative filtration markers and per 30% decline in eGFRCys , eGFR Cr-Cys , and eGFRCr-Cys-B2M were associated with clinical outcomes. Measurement of alternative filtration markers, particularly B2M in adults with type 2 diabetes may be warranted. This article is protected by copyright. All rights reserved.

Aim To examine possible sex differences in the excess risk of myocardial infarction (MI) consequent to a range of conventional risk factors in a large-scale international cohort of patients with diabetes, and to quantify these potential differences both on the relative and absolute scales. Materials and methods Eleven thousand and sixty-five participants (42% women) with type 2 diabetes in the ADVANCE trial and its post-trial follow-up study, ADVANCE-ON, were included. Cox regression models were used to estimate hazard ratios (HRs) for associations between risk factors and MI (fatal and non-fatal) by sex, and the women-to-men ratio of HRs (RHR). Results Over a median of 9.6 years of follow-up, 719 patients experienced MI. Smoking status, smoking intensity, higher systolic blood pressure (SBP), HbA1c, total and LDL cholesterol, duration of diabetes, triglycerides, body mass index (BMI) and lower HDL cholesterol were associated with an increased risk of MI in both sexes. Furthermore, some variables were associated with a greater relative risk of MI in women than men: RHRs were 1.75 (95% CI: 1.05-2.91) for current smoking, 1.53 (1.00-2.32) for former smoking, 1.18 (1.02-1.37) for SBP, and 1.13 (95% CI, 1.003-1.26) for duration of diabetes. Although incidence rates of MI were higher in men (9.3 per 1000 person-years) compared with women (5.8 per 1000 person-years), rate differences associated with risk factors were greater in women than men, except for HDL cholesterol and BMI. Conclusions In patients with type 2 diabetes, smoking, higher SBP and longer duration of diabetes had a greater relative and absolute effect in women than men, highlighting the importance of routine sex-specific approaches and early interventions in women with diabetes.

Stepwise escalation of glucose-lowering therapy to more intensive regimens is an integral component of type 2 diabetes management (1). Early blood glucose control is associated with beneficial effects on long-term micro- and macrovascular outcomes (2). Understanding factors associated with time to therapy escalation following an elevated glycated hemoglobin (HbA1c) may inform interventions to facilitate timely control. We used linked real-world data to examine time to therapy escalation following a recorded HbA1c ≥8.0% (64 mmol/mol) and associated factors. The EXamining ouTcomEs in chroNic Disease in the 45 and Up Study (EXTEND45 Study) is an Australian population-based linked data study in which participants of the 45 and Up Study have been linked to the Medicare Benefits Schedule (MBS), providing data on government-subsidized medical services, the Pharmaceutical Benefits Scheme (PBS), providing prescription claims data, and community laboratory databases (among others) (3). The 45 and Up Study comprises 267,153 individuals aged ≥45 years living in New South Wales (NSW), Australia, recruited between July 2006 and December 2009. Ethical approval for the EXTEND45 Study was obtained from the NSW Population & Health Services Research Ethics Committee (HREC/13/CIPHS/49). In EXTEND45, 24,430 individuals with diabetes between 2006 and 2014 have been identified using multiple linked data sources (3). In the current study, therapy escalation was assessed during the 6 months following all linked HbA1c results ≥8.0% occurring in non–treatment-naive, non–insulin-using individuals presumed to have type 2 diabetes. As a result, the unit of analysis was the elevated HbA1c, with individuals able to contribute multiple results to the analysis. A threshold of 8.0% was used to reflect the typically higher HbA1c targets recommended for older people (4). To ensure that all included HbA1c results represented separate instances of an elevated HbA1c in the same individual, those results ≥8.0% that occurred …

Many studies have demonstrated that monotherapy with tenofovir disoproxil fumarate (TDF) or entecavir (ETV) can reduce the risk of liver complications in individuals chronically infected with HBV (CHB). Unclear is whether one monotherapy is more effective than the other at preventing these outcomes. In a recent issue of this journal, Lee and coworkers1 reported data from a large population of treatment-naive CHB patients in which risk of hepatocellular carcinoma (HCC), all-cause mortality or liver transplantation was similar with either monotherapy. Similar results were observed in subgroups of patients with chronic hepatitis or cirrhosis. While this study involved more than 7000 South Korean patients who were enrolled during more than a decade and whose virological and biochemical data over several years were analysed, its findings must be treated with caution because the two groups differed substantially in median …

AIM: The use of sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) has been limited, primarily because glycemic efficacy is dependent on kidney function. We performed a systematic review and meta-analysis to assess the efficacy and safety of SGLT2 inhibitors in patients with T2DM and CKD, defined as estimated glomerular filtration rate (eGFR) MATERIALS AND METHODS: We searched MEDLINE, EMBASE and the Cochrane Library to August 7, 2018, as well as the websites of the United States, European, and Japanese regulatory authorities to July 27, 2018 for data from randomized controlled trials of SGLT2 inhibitors that included reporting of effects on biomarkers, cardiovascular, renal, or safety outcomes in individuals with T2DM and CKD. Random effects models and inverse variance weighting were used to calculate relative risks with 95% confidence intervals.RESULTS: Data were obtained from 27 studies with up to 7,363 participants contributing. In patients with T2DM and CKD, SGLT2 inhibitors lowered glycated hemoglobin (-0.29%, 95% CI -0.39 to -0.19), as well as blood pressure, body weight, and albuminuria. SGLT2 inhibition reduced the risk of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (RR 0.81, 95% CI 0.70-0.94) and heart failure (RR 0.61, 95% CI 0.48-0.78), without a clear effect on all-cause mortality (HR 0.86, 95% CI 0.73-1.01). These agents also attenuated the annual decline in eGFR slope (placebo-subtracted difference of 1.35 mL/1.73m2 /year, 95% CI 0.78-1.93) and reduced the risk of the composite renal outcome (HR 0.71, 95% CI 0.53-0.95). There was no evidence of additional risks with SGLT2 inhibition in CKD beyond those already known for the class, although heterogeneity was observed across individual agents for some safety outcomes.CONCLUSION: Currently available data suggest that despite only modest reductions in glycated hemoglobin, SGLT2 inhibitors reduce the risk of cardiovascular and renal outcomes in patients with T2DM and CKD, without clear evidence of additional safety concerns. This article is protected by copyright. All rights reserved.

Inflammation in tumor microenvironments is implicated in the pathogenesis of tumor development. In particular, inflammasomes, which modulate innate immune functions, are linked to tumor growth and anticancer responses. However, the role of the NLRC4 inflammasome in gliomas remains unclear. Here, we investigated whether the upregulation of the NLRC4 inflammasome is associated with the clinical prognosis of gliomas. We analyzed the protein expression and localization of NLRC4 in glioma tissues from 11 patients by immunohistochemistry. We examined the interaction between the expression of NLRC4 and clinical prognosis via a Kaplan-Meier survival analysis. The level of NLRC4 protein was increased in brain tissues, specifically, in astrocytes, from glioma patients. NLRC4 expression was associated with a poor prognosis in glioma patients, and the upregulation of NLRC4 in astrocytomas was associated with poor survival. Furthermore, hierarchical clustering of data from the Cancer Genome Atlas dataset showed that NLRC4 was highly expressed in gliomas relative to that in a normal healthy group. Our results suggest that the upregulation of the NLRC4 inflammasome contributes to a poor prognosis for gliomas and presents a potential therapeutic target and diagnostic marker.

Background There is ongoing controversy around the surrogacy of proteinuria or albuminuria, particularly for cardiovascular (CV) outcomes, which remain the leading cause of morbidity and mortality among patients with chronic kidney disease. We performed a systematic review and meta-analysis of the literature to assess the surrogacy of changing proteinuria or albuminuria for CV events, end-stage renal disease (ESRD), and all-cause mortality. Methods CENTRAL, EMBASE, and MEDLINE were searched (from inception to October 2017). All randomized controlled trials in adults that reported change in proteinuria or albuminuria and ≥ 10 CV, ESRD, or all-cause mortality events were included. We calculated treatment effect ratios (TERs), defined as the ratio of the treatment effect on a clinical outcome and the effect on the change in the surrogate outcome. TERs close to 1 indicate greater agreement between the clinical outcome and changing proteinuria or albuminuria. Results Thirty-six trials were included in the meta-analysis. We observed inconsistent treatment effects for proteinuria and CV events (20 trials; TER 1.11 [95% confidence interval (CI), 1.01-1.22]) with moderate heterogeneity (I2 = 51%, P = 0.005). Treatment effects on proteinuria or albuminuria were also inconsistent with the effects on all-cause mortality (21 trials; TER 1.17 [95% CI, 1.07-1.28]; I2 = 35%, P for heterogeneity = 0.06), although they were similar with the effects on ESRD (23 trials; TER 0.99 [95% CI, 0.88-1.13]; I2 = 9%, P for heterogeneity = 0.337). Conclusions Change in proteinuria or albuminuria might be a suitable surrogate outcome for ESRD. However, overall treatment effects on these potential surrogates are inconsistent and overestimate the treatment effects on CV events and all-cause mortality.

Diet plays a major role in regulating cancer. Bioactives such as polyphenols and isoflavones found naturally in our food are increasingly being recognised as regulators of interest. These compounds can regulate cancer pathways through microRNAs which are critical in modulating expression of various genes. We carried out a literature review wherein we assessed the impact of three dietary compounds, namely butyrate, genistein and quercetin, on miRNA expression followed by an in silico study utilising DIANA-miRPathv3 software. Our literature search found that miR-34a, miR-200a-3p and miR-200b-3p were modulated by all three compounds while miR-221, miR-222, miR-29a, miR-3935 and miR-574-3p were modulated by both genistein and butyrate and let-7b, miR-194, miR-96-5p and miR-424 were modulated by butyrate and quercetin. The in silico analysis identified key pathways of interest such as “bladder cancer” which had significant interactions with the miRNAs modulated by the dietary compounds.

Purpose: To evaluate the compatibility of corneal curvature and astigmatism, and higher-order aberrations (HOAs) measured by the Scheimpflug camera Pentacam HR and the swept-source optical coherence tomography ANTERION.Methods: This prospective study included normal subjects with no ophthalmic history. Steep keratometry (K), flat K, astigmatism and its axis of the anterior and posterior surfaces, total corneal power, and HOAs using the two instruments were compared. To compare the mean values of the measurements, a paired t-test was used. Bland-Altman analysis was applied to assess the agreement between the two devices.Results: Fifty-three eyes of 53 subjects were evaluated. There were statistically significant differences for steep K, astigmatism, and vector J0, J45 in the anterior surface and total corneal power between the two devices (p < 0.05). There were also significant differences in the most of the keratometric values of the posterior corneal surface (p < 0.05) except J0 (p = 0.410). Both devices showed strong positive correlations in steep K, flat K, astigmatism (r > 0.81, p < 0.001) with wide ranges of a 95% limit of agreement. Vectoral components were significantly correlated (r > 0.78, p < 0.001) with narrow 95% limit of agreement, except J45 of the posterior surface (r = 0.39, p = 0.004). In the corneal HOAs, there were statistically significant differences in the vertical coma, horizontal trefoil, spherical aberration, and root mean square of each fifth- and sixth-order Zernike coefficient (p = 0.043, p = 0.041, p < 0.001, p < 0.001, and p < 0.001, respectively). Other HOAs showed moderate to strong positive correlations (r > 0.37, p < 0.05). Most HOAs, except for the horizontal trefoil, showed clinically acceptable agreements. The total root mean square of HOAs was not significantly different between the two devices (p = 0.122).Conclusions: Most of the keratometric values cannot be used interchangeably. However, the vectoral component of astigmatism showed clinically good agreement. Several HOAs have statistically significant differences; however, almost all HOAs showed acceptable agreements, except for the horizontal trefoil.

Background and objectives Anticoagulation with either a vitamin K antagonist or a direct oral anticoagulant may be associated with AKI. Our objective was to assess the risk of AKI among elderly individuals with atrial fibrillation newly prescribed a direct oral anticoagulant (dabigatran, rivaroxaban, or apixaban) versus warfarin. Design, setting, participants, & measurements Our population-based cohort study included 20,683 outpatients in Ontario, Canada, ≥66 years with atrial fibrillation who were prescribed warfarin, dabigatran, rivaroxaban, or apixaban between 2009 and 2017. Inverse probability of treatment weighting on the basis of derived propensity scores for the treatment with each direct oral anticoagulant was used to balance baseline characteristics among patients receiving each of the three direct oral anticoagulants compared with warfarin. Cox proportional hazards regression was performed in the weighted population to compare the association between the prescribed anticoagulant and the outcomes of interest. The exposure was an outpatient prescription of warfarin or one of the direct oral anticoagulants. The primary outcome was a hospital encounter with AKI, defined using Kidney Disease Improving Global Outcomes thresholds. Prespecified subgroup analyses were conducted by eGFR category and by the percentage of international normalized ratio measurements in range, a validated marker of anticoagulation control. Results Each direct oral anticoagulant was associated with a significantly lower risk of AKI compared with warfarin (weighted hazard ratio, 0.65; 95% confidence interval, 0.53 to 0.80 for dabigatran; weighted hazard ratio, 0.85; 95% confidence interval, 0.73 to 0.98 for rivaroxaban; and weighted hazard ratio, 0.81; 95% confidence interval, 0.72 to 0.93 for apixaban). In the subgroup analysis, the lower risk of AKI associated with each direct oral anticoagulant was consistent across each eGFR strata. The risk of AKI was significantly lower among users of each of the direct oral anticoagulants compared with warfarin users who had a percentage of international normalized ratio measurements ≤56%. Conclusions Direct oral anticoagulants were associated with a lower risk of AKI compared with warfarin.

There have been no large-scale studies on the epidemiology of benign convulsions with mild gastroenteritis (CwG) since the introduction of the rotavirus vaccine in South Korea in 2007. This study aimed to analyze the trends in rotavirus gastroenteritis (RVGE) and rotavirus-associated CwG (RaCwG) after rotavirus vaccination. Further, we aimed to analyze changes in norovirus gastroenteritis (NVGE) and norovirus-associated CwG (NaCwG) using nationwide data from the Korean Health Insurance Review and Assessment Service. Between 2007 and 2019, this study analyzed children aged &lt, 6 years who were diagnosed with RVGE, NVGE, RaCwG and NaCwG. The changes in the prevalence of each disease and the ratio of CwG to enteritis were analyzed and the effects of age, sex and season were also analyzed. RVGE, RaCwG, NVGE and NaCwG were diagnosed in 273,898, 4246, 35,593 and 337 patients, respectively. The prevalence of RVGE was on a decreasing trend every year, but the prevalence of NaCwG and NVGE was on an increasing trend. There was a significant annual increase in the ratio of CwG to enteritis in both viruses. In order to control the prevalence of RaCwG, measures other than the rotavirus vaccine are required and measures to prevent norovirus are necessary.

Glioblastoma is the most common and aggressive brain tumor and it is characterized by a high mortality rate. Temozolomide (TMZ) is an effective chemotherapy drug for glioblastoma, but the resistance to TMZ has come to represent a major clinical problem, and its underlying mechanism has yet to be elucidated. In the present study, the role of exosomal connexin 43 (Cx43) in the resistance of glioma cells to TMZ and cell migration was investigated. First, higher expression levels of Cx43 were detected in TMZ-resistant U251 (U251r) cells compared with those in TMZ-sensitive (U251s) cells. Exosomes from U251s or U251r cells (sExo and rExo, respectively) were isolated. It was found that the expression of Cx43 in rExo was notably higher compared with that in sExo, whereas treatment with rExo increased the expression of Cx43 in U251s cells. Additionally, exosomes stained with dioctadecyloxacarbocyanine (Dio) were used to visualized exosome uptake by glioma cells. It was observed that the uptake of Dio-stained rExo in U251s cells was more prominent compared with that of Dio-stained sExo, while 37,43Gap27, a gap junction mimetic peptide directed against Cx43, alleviated the rExo uptake by cells. Moreover, rExo increased the IC50 of U251s to TMZ, colony formation and Bcl-2 expression, but decreased Bax and cleaved caspase-3 expression in U251s cells. 37,43Gap27 efficiently inhibited these effects of rExo on U251s cells. Finally, the results of the wound healing and Transwell assays revealed that rExo significantly enhanced the migration of U251s cells, whereas 37,43Gap27 significantly attenuated rExo-induced cell migration. Taken together, these results indicate the crucial role of exosomal Cx43 in chemotherapy resistance and migration of glioma cells, and suggest that Cx43 may hold promise as a therapeutic target for glioblastoma in the future.

Objective To assess the safety and efficacy of prostatic arterial embolization (PAE) for elderly patients with lower urinary tract symptoms secondary to large benign prostatic hyperplasia. Methods Twenty-eight patients (>80 years of age) with prostate volume >80 mL were enrolled from October 2016 to October 2019. PAE was performed using microspheres and functional results were evaluated at 1, 3, 6, and 12 months postoperatively. The following data were recorded: International Prostate Symptom Score (IPSS), quality of life (QoL), maximum urine flow rate (Qmax), post-void residual urine volume, prostate volume and total prostate-specific antigen level. Results Selective prostatic arterial catheterization and embolization were achieved in 27 of 28 patients. Follow-up data were available for those 27 patients until 12 months postoperatively. Significant improvements were found at all postoperative time points in terms of the mean IPSS, mean QoL score, mean Qmax, mean post-void residual urine volume, mean total prostate-specific antigen level, and mean prostate volume. The overall complication rate was 46.4%. Conclusions PAE is an efficacious and safe treatment for elderly patients with large prostate volume; it may offer an effective approach for patients who are not candidates for open or endoscopic surgical procedures because of comorbidities.

Background Direct oral anticoagulants (DOACs) have widely replaced warfarin for stroke prevention in nonvalvular atrial fibrillation. Our objective was to compare the safety and effectiveness of DOACs (dabigatran, rivaroxaban, apixaban) versus warfarin for stroke prevention in nonvalvular atrial fibrillation in the Canadian setting. Methods We conducted a population-based observational multicentre cohort study with propensity score matching and subsequent meta-analysis. We used health care databases from 7 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba, Ontario, Quebec and Nova Scotia). Patients with nonvalvular atrial fibrillation who initiated anticoagulation therapy in 2009-2017 were matched to an equal number who initiated warfarin. The primary outcome was the pooled hazard ratio (HR) for ischemic stroke or systemic embolization. Secondary outcomes included pooled HRs for major bleeding; a composite outcome of stroke, systemic embolization, major bleeding and all-cause mortality; and myocardial infarction. We modelled HRs using proportional hazard Cox regression with inverse probability of censoring weights, and estimated pooled HRs with random-effect meta-analyses. Results We included 128 273 patients who initiated anticoagulation with a DOAC (40 503 dabigatran, 49 498 rivaroxaban and 38 272 apixaban) and 128 273 patients who initiated anticoagulation with warfarin. The pooled HR for ischemic stroke or systemic embolization comparing DOACs to warfarin was 1.02 (95% confidence interval [CI] 0.87 to 1.19). Direct oral anticoagulants were associated with lower rates of major bleeding (pooled HR 0.81, 95% CI 0.69 to 0.97), the composite outcome (pooled HR 0.81, 95% CI 0.74 to 0.89) and all-cause mortality (pooled HR 0.81, 95% CI 0.78 to 0.85). Interpretation In this real-world study, DOACs were associated with similar risks of ischemic stroke or systemic embolization, and lower risks of bleeding and total mortality compared to warfarin. These findings support the use of DOACs for anticoagulation in nonvalvular atrial fibrillation. Trial registration ClinicalTrials.gov, no. NCT03596502.

Min-Jun Wang,1,&ast; Jia-Jia Chen,1,&ast; Shao-Hua Song,2,&ast; Jing Su,1,&ast; Ling-Hao Zhao,3 Qing-Gui Liu,1 Tao Yang,1 Zhiwen Chen,4 Chang Liu,4 Zhi-Ren Fu,2 Yi-Ping Hu,1 Fei Chen1 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University (Navy Medical University), Shanghai, People’s Republic of China; 2Department of General Surgery, Liver Transplantation Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 3National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People’s Republic of China; 4State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fei Chen Yi-Ping HuDepartment of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, 800 Xiangyin Road, Shanghai, 200433, ChinaTel +86-21-81870943Email feelchen@smmu.edu.cn; yphu9@yeah.netPurpose: Cancer stem cells (CSCs) have been considered involving in tumorigenesis, local recurrence, and therapeutic drug resistance of hepatocellular carcinoma (HCC). To investigate novel and effective methods for targeting hepatic CSCs is crucial for a permanent cure of liver cancer.Methods: The expression level of SIRT1 was detected in CSCs of HCC tissues and cancer cell lines. Expression of CSC markers, the self-renewal and tumorigenic ability of liver CSCs were analyzed with SIRT1 inhibition. Cellular senescence-related markers were used to detect CSCs senescence after inhibition of SIRT1.Results: SIRT1 was highly expressed in CSCs of HCC cell lines and human HCC tissues. In vitro study revealed that decreasing of SIRT1 level significantly downregulated the stemness-associated genes of liver CSCs and reduced the CSC stemness properties. Also, downregulated SIRT1 suppressed liver CSCs proliferation by decreasing their self-renewal abilities. Furthermore, CSCs with decreased SIRT1 expression showed limited tumorigenicity and formed smaller HCC tumor in vivo. And SIRT1 decreased CSCs became more susceptible to chemotherapeutic drugs. Mechanistically, SIRT1 decreased CSCs became senescence through the activation of p53-p21 and p16 pathway. The data further indicated that the tumor formed from SIRT1-knockdown CSCs exhibited higher senescence-associated β-galactosidase (SA-β-Gal) activity but lower proliferative capacity.Conclusion: Taken together, these findings pointed that induction of senescence in liver CSCs is an effective tumor suppression method for HCC, and SIRT1 may be served as a promising target for HCC treatment.Keywords: SIRT1, hepatocellular carcinoma, liver cancer stem cells, cellular senescence, stemness, self-renewal

Aims To use linked routinely-collected health data to estimate diabetes prevalence and incidence in an Australian cohort of adults aged ≥45 years, and examine risk factors associated with incident disease. Research design and methods The EXamining ouTcomEs in chroNic Disease in the 45 and Up Study (EXTEND45) Study is a linked data study that combines baseline questionnaire responses from the population-based 45 and Up Study (2006–2009, n = 267,153) with multiple routinely-collected health databases up to December 2014. Among participants with ≥1 linked result for any laboratory test, diabetes status was determined from multiple data sources according to standard biochemical criteria, use of glucose-lowering medication or self-report, and the prevalence and incidence rate calculated. Independent risk factors of incident diabetes were examined using multivariable Cox regression. Results Among 152,169 45 and Up Study participants with ≥1 linked laboratory result in the EXTEND45 database (mean age 63.0 years; 54.9% female), diabetes prevalence was 10.8% (95% confidence interval [CI] 10.6%–10.9%). Incident disease in those without diabetes at baseline (n = 135,810; mean age 62.5 years; 56.1% female) was 10.0 per 1,000 person-years (95% CI 9.8–10.2). In all age groups, diabetes incidence was lower in women compared to men, an association that persisted in the fully adjusted analyses. Other independent risk factors of diabetes were older age, being born outside of Australia (with the highest rate of 19.2 per 1,000 person-years observed in people born in South and Central Asia), lower education status, lower annual household income, residence in a major city, family history of diabetes, personal history of cardiovascular disease or hypertension, higher body mass index, smoking and long sleeping hours. Conclusions Our study represents an efficient approach to assessing diabetes frequency and its risk factors in the community. The infrastructure provided by the EXTEND45 Study will be useful for diabetes surveillance and examining other important clinical and epidemiological questions.

Most studies addressing hemodialysis initiation with a dialysis catheter focus on patients entering maintenance dialysis programs and exclude other patients, such as those with acute kidney injury (AKI), making interpretation and application of the results difficult for clinicians managing patients at the time of dialysis commencement.To compare the survival of all patients requiring a catheter for hemodialysis access according to the nature of clinical presentation.Prospective observational.An Australian tertiary renal unit.All patients requiring a central venous catheter (CVC) for hemodialysis access between 2005 and 2015.Baseline comorbidities, demographics, and nature of clinical presentation. Data regarding each episode of dialysis access insufficiency and each CVC were collected. The primary outcome was all-cause mortality.Patients were classified into 1 of 3 groups based on physician assessment at the time of presentation: patients believed to have AKI with expected renal recovery (AKI), patients considered to be entering the maintenance dialysis program without a functioning dialysis access (Maintenance Dialysis), patients unable to perform peritoneal dialysis, or use their existing hemodialysis access (Access Failure). Time-split multivariable Cox regression analyses were used to compare survival between groups.A total of 557 eligible patients had complete prospective data regarding CVC use and were included in the analyses. The majority of patients were in the AKI (246/557, 44%) and Maintenance Dialysis groups (182/557, 33%) compared with the Access Failure group (129/557, 23%). During a median follow-up of 3 years, 302 (54%) of the 557 patients died. Following adjustment, risk of all-cause mortality was higher in the AKI group (hazard ratio [HR]: 2.01, 95% confidence interval [CI]: 1.31-3.60,Single-center study. Possible residual confounding owing to the observational study design.Patients requiring acute or unplanned hemodialysis experience high mortality, and the nature of clinical presentation does influence outcomes. Most notable is the greater early mortality experienced by patients with AKI compared to other patient groups. Prospective definition of the nature of unplanned dialysis initiation is important to accurately measure and improve outcomes in this high-risk patient population.CH62/6/2017-042.La plupart des études traitant de l’initiation d’un traitement d’hémodialyse avec cathéter portent sur des patients qui s’engagent dans un program de dialyze d’entretien et excluent les autres patients, notamment ceux atteints d’insuffisance rénale aiguë (IRA). Ceci rend difficiles l’interprétation et l’application des résultats pour les cliniciens qui traitent les patients à l’amorce de la dialyze.Comparer la survie de tous les patients nécessitant un cathéter pour l’accès à l’hémodialyse selon la nature du tableau clinique.Étude observationnelle prospective.L’unité de néphrologie d’un center de soins tertiaires australien.Tous les patients qui, entre 2005 et 2015, ont eu besoin d’un cathéter veineux central (CVC) pour l’hémodialyse.Les maladies concomitantes existantes et les données démographiques des patients, ainsi que la nature du tableau clinique. Les données concernant chaque CVC et épisode d’accès déficient ont été recueillies. Le principal critère de jugement était la mortalité toutes causes confondues.Les patients ont été répartis dans trois groupes selon l’évaluation du médecin au moment de la présentation : patients soupçonnés d’IRA avec récupération rénale prévue (groupe « IRA »), patients sans accès fonctionnel pour la dialyze considérés comme entrant dans le program de dialyze d’entretien (groupe « dialyze d’entretien »), et les patients incapables de pratiquer la dialyze péritonéale ou d’utiliser leur accès vasculaire existant (groupe « échec de l’accès »). Des régressions de Cox multivariées à temps partagé ont été utilisées pour comparer la survie entre les groupes.Ont été inclus dans les analyses les 557 patients admissibles pour lesquels on disposait de données prospectives complètes sur l’utilization d’un CVC. La majorité des patients se trouvaient dans les groupes « IRA » (246/557; 44 %) et « dialyze d’entretien » (182/557; 33 %); le groupe « échec de l’accès » ne représentant que 23 % des patients inclus (129/557). Au cours d’un suivi médian de trois ans, 302 patients (54 %) sont décédés. Après correction, le risque de mortalité toutes causes confondues dans les deux premières années suivant l’insertion du cathéter était plus élevé dans le groupe IRA (RR : 2,01; IC à 95 % : 1,31-3,60;L’étude est monocentrique et la nature observationnelle de l’étude sous-tend de possibles facteurs de confusion résiduels.Les patients nécessitant une hémodialyse aiguë ou non planifiée connaissent un taux de mortalité élevé, et la nature du tableau clinique influence les résultats. Le plus remarquable étant la mortalité précoce plus élevée des patients atteints d’IRA comparativement aux autres patients. Il est important de définir la nature prospective de l’amorce non planifiée de la dialyze afin de mesurer précisément les résultats dans cette population à haut risque, et de les améliorer.

Background Autoantibody production against endogenous cellular components is pathogenic feature of systemic lupus erythematosus (SLE). Follicular helper T (TFH) cells aid in B cell differentiation into autoantibody-producing plasma cells (PCs). The IL-6 and IL-21 cytokine-mediated STAT3 signaling are crucial for the differentiation to TFH cells. Niclosamide is an anti-helminthic drug used to treat parasitic infections but also exhibits a therapeutic effect on autoimmune diseases due to its potential immune regulatory effects. In this study, we examined whether niclosamide treatment could relieve lupus-like autoimmunity by modulating the differentiation of TFH cells in two murine models of lupus. Methods 10-week-old MRL/lpr mice were orally administered with 100 mg/kg of niclosamide or with 0.5% methylcellulose (MC, vehicle) daily for 7 weeks. TLR7 agonist, resiquimod was topically applied to an ear of 8-week-old C57BL/6 mice 3 times a week for 5 weeks. And they were orally administered with 100 mg/kg of niclosamide or with 0.5% MC daily for 5 weeks. Every mouse was analyzed for lupus nephritis, proteinuria, autoantibodies, immune complex, immune cell subsets at the time of the euthanization. Results Niclosamide treatment greatly improved proteinuria, anti-dsDNA antibody levels, immunoglobulin subclass titers, histology of lupus nephritis, and C3 deposition in MRL/lpr and R848-induced mice. In addition, niclosamide inhibited the proportion of TFH cells and PCs in the spleens of these animals, and effectively suppressed differentiation of TFH-like cells and expression of associated genes in vitro. Conclusions Niclosamide exerted therapeutic effects on murine lupus models by suppressing TFH cells and plasma cells through STAT3 inhibition.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which the main contributors to organ damage are antibodies against autoantigens, such as double-stranded DNA (dsDNA). Calorie restriction and intermittent fasting (IF) have been shown to improve autoimmune disease symptoms in patients and animal models. Here, we tested the hypothesis that IF might improve symptoms in MRL/lpr mice, which spontaneously develop an SLE-like disease. Groups of mice were fed every other day (IF) or provided food ad libitum (controls), and various lupus-associated clinicopathological parameters were analyzed for up to 28 weeks. Contrary to expectations, anti-dsDNA antibody levels, immune complex deposition in the kidney, and glomerular injury were higher in the IF group than the control group, although there were no differences in spleen and lymph node weights between groups. Proteinuria was also worsened in the IF group. IF also increased the abundance of B cells, plasmablasts, and plasma cells and elevated autophagy in plasma cells in the spleen and lymph nodes. Secretion of anti-dsDNA antibody by splenocytes in vitro was reduced by chloroquine-induced inhibition of autophagy. These results suggest that IF exacerbates lupus nephritis in MRL/lpr mice by increasing autoantibody immune complex formation.

Background There are conflicting signals in the literature about comparative safety and effectiveness of direct oral anticoagulants (DOACs) for non-valvular atrial fibrillation (NVAF). Methods We conducted multi-center matched cohort studies with secondary meta-analysis to assess safety and effectiveness of dabigatran, rivaroxaban and apixaban across 9 administrative healthcare databases. We included adults with NVAF initiating anticoagulation therapy (dabigatran, rivaroxaban, or apixaban), and constructed 3 cohorts to compare DOACs pairwise. The primary outcome was pooled hazard ratio (pHR) of ischemic stroke or systemic thromboembolism. Secondary outcomes included pHR of major bleeding, and a composite of stroke, major bleeding, or all-cause mortality. We used proportional hazard Cox regressions models, and pooled estimates were obtained with random effect meta-analyses. Results The cohorts included 73,414 new users of dabigatran, 92,881 of rivaroxaban, and 61,284 of apixaban. After matching, the pHRs (95% confidence intervals) comparing rivaroxaban initiation to dabigatran were: 1.11 (0.93, 1.32) for ischemic stroke or systemic thromboembolism, 1.26 (1.09, 1.46) for major bleeding, and 1.17 (1.05, 1.30) for the composite endpoint. For apixaban vs dabigatran, they were: 0.91 (0.74, 1.12) for ischemic stroke or systemic thromboembolism, 0.89 (0.75, 1.05) for major bleeding, and 0.94 (0.78 to 1.14) for the composite endpoint. For apixaban vs rivaroxaban, they were: 0.85 (0.74, 0.99) for ischemic stroke or systemic thromboembolism, 0.61 (0.53, 0.70) for major bleeding, and 0.82 (0.76, 0.88) for the composite endpoint. Conclusion We found that apixaban use is associated with lower risks of stroke and bleeding compared with rivaroxaban, and similar risks compared with dabigatran.

Introduction Several circulating markers, including autoantibodies to erythropoietin receptor (anti-EPOR antibodies), have been identified as useful biomarkers in predicting diabetic kidney disease progression. However, a direct comparison of their utility is lacking. We aimed to validate and to compare the prognostic value of anti-EPOR antibodies with that of other known biomarkers, using the ADVANCE trial and its long-term follow-up, ADVANCE-ON, cohorts. Methods In this nested case-control study from the ADVANCE trial cohort, we included 165 case participants who had the composite kidney outcome (renal replacement therapy, renal death, or doubling of serum creatinine to ≥200 μmol/l) and 330 matched controls. We compared the associations of baseline plasma levels of anti-EPOR antibodies, tumor necrosis factor receptor (TNFR)-1 and -2, and bone morphogenetic protein (BMP)-7 with kidney outcomes. Results Cases had higher baseline plasma levels of anti-EPOR antibodies than controls (median 1.7 vs. 0.6 enzyme-linked immunosorbent assay unit, P < 0.001). Higher levels of anti-EPOR antibodies were associated with an increased risk of kidney outcome (odds ratio 2.16 [95% confidence interval 1.51, 3.08], per 1 SD of log-transformed levels) after adjusting for conventional markers. Elevated circulating TNFR1 and TNFR2 levels, and lower BMP-7 levels at baseline, were associated with poor kidney outcome (odds ratios 2.06 [1.29, 3.30], 1.66 [1.13, 2.43], and 0.45 [0.32, 0.65], respectively). The addition of anti-EPOR antibodies into the model improved the prediction of kidney outcome, regardless of other biomarkers. Conclusion Anti-EPOR antibodies provide a promising biomarker, as with TNFR1, TNFR2, and BMP-7, in predicting kidney disease progression in people with type 2 diabetes mellitus., Graphical abstract

AIMS To summarize evidence from randomized controlled trials (RCTs) concerning the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on kidney outcomes in patients with type 2 diabetes mellitus (T2DM). METHODS The Medline, EMBASE and Cochrane databases were searched for RCTs comparing DPP-4 inhibitors with a placebo, active comparator or standard care, with at least 500 person-years follow-up in patients with T2DM and with reporting of kidney outcomes. Treatment effects were summarized using random-effects meta-analysis. RESULTS Ten trials including 47 955 patients (mean estimated glomerular filtration rate [eGFR] 71 mL/min/1.73m2 , mean follow-up 10 762 patient-years per trial) were eligible for inclusion. DPP-4 inhibitors were compared with placebo (five trials), active comparator (three trials), and standard care (two trials). Overall, treatment with DPP-4 inhibitors was associated with a greater decline in eGFR than treatment with the comparators (weighted mean difference -1.12 mL/min/1.73m2 , 95% confidence interval [CI] -1.61, -0.62; high-certainty evidence). There were no detectable effects of DPP-4 inhibitors on rates of doubling serum creatinine (risk ratio [RR] 1.10, 95% CI 0.90, 1.34; high-certainty evidence), end-stage kidney disease (RR 0.97, 95% CI 0.77, 1.23; high-certainty evidence), death from kidney causes (RR 1.81, 95% CI 0.67, 4.93; low-certainty evidence), or all-cause mortality (RR 1.01, 95% CI 0.95, 1.09; high-certainty evidence). DPP-4 inhibitors significantly reduced the risks of the surrogate kidney outcome of new albuminuria (RR 0.88, 95% CI 0.8, 0.98; moderate-certainty evidence) and worsening albuminuria (RR 0.88, 95% CI 0.82, 0.94; moderate-certainty evidence). There was no difference in the safety outcome of acute kidney injury (RR 1.04, 95% CI 0.57, 1.87; high-certainty evidence). CONCLUSIONS Dipeptidyl peptidase-4 inhibitors are associated with a greater decline in eGFR, despite reducing the development and progression of albuminuria, and have no clear effect on other key kidney outcomes.

Aims/hypothesis This biomarker study aimed to quantify the association of essential and other plasma fatty acid biomarkers with macrovascular disease, microvascular disease and death in individuals with type 2 diabetes. Methods A case-cohort study (N = 3576), including 654 macrovascular events, 341 microvascular events and 631 deaths during 5 years of (median) follow-up, was undertaken as a secondary analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) study (full details of the study design and primary endpoints of the ADVANCE trial and its case-cohort have been published previously). This current study considers new data: fatty acids measured from baseline plasma samples by proton NMR analysis. The fatty acids measured were n-3, docosahexaenoic acid (DHA), n-6, linoleic acid, and polyunsaturated, monounsaturated and saturated fatty acids. HRs were modelled per SD higher (percentage) fatty acid. C statistics and continuous net reclassification improvement were used to test the added value of fatty acids compared with traditional cardiovascular risk factors. Results After adjustment for traditional cardiovascular risk factors, an inverse association was observed for n-3 fatty acids and DHA with the risk of macrovascular events (HR [95% CI]: 0.87 [0.80, 0.95] and 0.88 [0.81, 0.96], respectively, per 1 SD higher percentage), and for n-3 fatty acids with the risk of death (HR 0.91 [95% CI 0.84, 0.99] per 1 SD higher percentage). Such associations were also evident when investigating absolute levels of fatty acids. There were no statistically significant associations between any fatty acids and microvascular disease after adjustment. However, there was limited improvement in the predictive ability of models when any fatty acid was added. Conclusions/interpretation Plasma n-3 fatty acids and DHA were found to be inversely associated with macrovascular disease, while n-3 fatty acids were also inversely associated with death. These results support the cardioprotective effects of n-3 fatty acids and DHA and further merit testing the role of high-dose supplementation with n-3 fatty acids in individuals with type 2 diabetes. Trial registration ClinicalTrials.gov NCT00145925.

OBJECTIVE To determine the incidence of and factors associated with an estimated glomerular filtration rate (eGFR) RESEARCH DESIGN AND METHODS We identified people with diabetes in the EXamining ouTcomEs in chroNic Disease in the 45 and Up Study (EXTEND45), a population-based cohort study (2006–2014) that linked the Sax Institute’s 45 and Up Study cohort to community laboratory and administrative data in New South Wales, Australia. The study outcome was the first eGFR measurement RESULTS Of 9,313 participants with diabetes, 2,106 (22.6%) developed incident eGFR CONCLUSIONS In participants with diabetes, the incidence of an eGFR

Recent findings from The Cancer Genome Atlas project have provided a comprehensive map of genomic alterations that occur in hepatocellular carcinoma (HCC), including unexpected mutations in apolipoprotein B (APOB). We aimed to determine the clinical significance of this non-oncogenetic mutation in HCC. An Apob gene signature was derived from genes that differed between control mice and mice treated with siRNA specific for Apob (1.5-fold difference; P, Cancer: Spotlighting hidden cancer-causing genes Mutation of a gene with no clear role in tumor development triggers a cascade of reactions that can cause liver cancer. Recent genome-wide analyses searching for genes connected to development of hepatocellular carcinoma, the most common type of liver cancer, have turned up some unexpected genes, such as the fat metabolism gene apolipoprotein A (APOB). To discover how APOB is related to liver tumor development, Sun Young Yim at the University of Texas MD Anderson Cancer Center, Houston, USA, and coworkers compared whole-genome profiles from human cancer patients with those of mice, in which cancer-related genetic patterns are better characterized. They found that mutation of APOB was associated with switching on of cancer-promoting genes, and switching off of genes that suppress tumor growth. These results reveal a behind-the-scenes regulator of cancer development.

The purpose of this randomized clinical trial is to evaluate the effect of eyelid hygiene on subjective symptoms, anterior blepharitis, and meibomian gland dysfunction (MGD) after cataract surgery. Subjects with obstructive MGD who underwent cataract surgery were randomly divided into two groups. In the eyelid hygiene group, eyelid hygiene was performed twice a day for 10 days from 3 days before to 1 week after cataract surgery. The control group did not perform eyelid hygiene. A subjective symptom questionnaire of SPEED, anterior blepharitis grade, and meibum quality and quantity was evaluated at baseline and at postoperative 1 and 4 weeks. The eyelid hygiene group (n = 36) showed decreased SPEED score after cataract surgery and the control group (n = 33) did not. Anterior blepharitis grade was worse 1 week after surgery in the control group but not in the eyelid hygiene group. The control group had significantly decreased meibum quality and quantity in both the upper and lower eyelids after cataract surgery, but the eyelid hygiene group did not. Eyelid hygiene before/after cataract surgery improved postoperative subjective symptoms and prevented postoperative exacerbation of anterior blepharitis and MGD. Thus, perioperative eyelid hygiene is recommended for patients with obstructive MGD who undergo cataract surgery.

Background Calciphylaxis is a severe complication of advanced chronic kidney disease (CKD). Sodium thiosulphate (STS), an antioxidant and calcium chelating agent, has been used for the treatment of calciphylaxis. However, its efficacy and safety have not been systematically analysed and evaluated. Methods MEDLINE, EMBASE, and the Cochrane Library database were systematically searched for case report or cases series on use of STS for calciphylaxis published between July 1974 and October 2016. We extracted data on clinical characteristics, laboratory tests result and medication use. The effective treatment was defined as improvement in skin lesion cicatrisation or pain relief without death; Non-responding effects were defined as stable skin lesions without remission or exacerbation of the disease in patients who remained alive; All-cause mortality after STS treatment was defined as death due to exacerbations of calciphylaxis or other complications of advanced CKD. We compared the baseline parameters of the patients as well as the efficacy and mortality of the STS therapy between case report and multi-case reports. Statistical analyses were performed using SPSS 19. Results A total of 83 papers were screened, 45 of them (n = 358) met the inclusion criteria, including 36 case reports (n = 64) and 9 multi-case reports (n = 294). The mean age of the patients with calciphylaxis was 58 ± 14 years (range 26 - 91 years). They were female predominant, accounting for 74.1%. Among the patients with calciphylaxis, 96.1% patients were on dialysis with median dialysis vintage of 44.5 months (range 24 – 84 months). STS was effective in 70.1% of patients, 37.6% patients died. The proportion of patients with sepsis was higher among those who received intravenous STS. There was no significant difference in efficacy between the different STS administration methods (P = 0.19). Conclusion Although the study was unable to assess the efficacy of sodium thiosulphate alone in the treatment of calciphylaxis, it still reveals a promising role of STS as an effective therapy for calciphylaxis. Further prospective studies to define the optimal therapy for calciphylaxis are needed.

Genome-wide association studies have identified more than 90 susceptibility loci for breast cancer. However, the missing heritability is evident, and the contributions of coding variants to breast cancer susceptibility have not yet been systematically evaluated. Here, we present a large-scale whole-exome association study for breast cancer consisting of 24,162 individuals (10,055 cases and 14,107 controls). In addition to replicating known susceptibility loci (e.g., ESR1, FGFR2, and TOX3), we identify two novel missense variants in C21orf58 (rs13047478, Pmeta = 4.52 × 10−8) and ZNF526 (rs3810151, Pmeta = 7.60 × 10−9) and one new noncoding variant at 7q21.11 (P < 5 × 10−8). C21orf58 and ZNF526 possessed functional roles in the control of breast cancer cell growth, and the two coding variants were found to be the eQTL for several nearby genes. rs13047478 was significantly (P < 5.00 × 10−8) associated with the expression of genes MCM3AP and YBEY in breast mammary tissues. rs3810151 was found to be significantly associated with the expression of genes PAFAH1B3 (P = 8.39 × 10−8) and CNFN (P = 3.77 × 10−4) in human blood samples. C21orf58 and ZNF526, together with these eQTL genes, were differentially expressed in breast tumors versus normal breast. Our study reveals additional loci and novel genes for genetic predisposition to breast cancer and highlights a polygenic basis of disease development. Significance: Large-scale genetic screening identifies novel missense variants and a noncoding variant as predisposing factors for breast cancer. Cancer Res; 78(11); 3087–97. ©2018 AACR.

Li-Hua Yang,1,2,* Ye Wang,1,3,* Shi Qiao,1,* Min-Jun Wang,1 Fei Chen,1 Xiao-Yuan Zi,1 Jian-Xiu Li,1 Hai-Bin Zhang,4 Bing Yu,1,4 Yi-Ping Hu1 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai, People’s Republic of China; 2Department of Cell Biology and Neurobiology, Xuzhou Medical University, Xuzhou, People’s Republic of China; 3Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, People’s Republic of China; 4Department of Hepatic Surgery V, Eastern Hepatobiliary Surgery Hospital, Shanghai, People’s Republic of China *These authors contributed equally to this work Purpose: Liver cancer stem cells (CSCs) are known to be associated with the development, survival, proliferation, metastasis, and recurrence of liver tumors. The aim of this study was to investigate the association of liver-enriched activator protein 1 (LAP1) with hepatocellular carcinoma (HCC) and liver CSCs (LCSCs) and explore the impact of LAP1 on LCSCs. Materials and methods: Differences in LAP1 expression in liver cancer tissues versus matched para-tumoral liver tissues and LCSCs versus non-CSCs were analyzed by Western blotting, real-time polymerase chain reaction, immunohistochemistry, and flow cytometry. The effect of LAP1 on liver cancer cells was evaluated by the expression of CSC markers, oncosphere formation, proliferation, migration, and invasion in vitro. Cell cycle distribution and the number of apoptotic cells were analyzed to assess cell cycle and cell apoptosis. Furthermore, a mouse subcutaneous tumor implant model was established to explore the role of LAP1 in the development of HCC in vivo. Finally, the expression of CSC markers in paraffin-embedded sections was evaluated by immunofluorescence. Results: LAP1 was weakly expressed in HCC tumors and cell lines and even weaker in LCSCs. LAP1 inhibited the expression of stem cell–associated genes and reduced the abilities of oncosphere formation, proliferation, migration, and invasion in vitro. Cell cycle assay revealed that LAP1 induced G1/G0 arrest. Furthermore, LAP1 decreased subcutaneous tumor-formation ability and the expression of CSC markers and Ki67 in vivo. Conclusion: LAP1 suppressed the stem cell features of HCC, indicating that it possessed an antitumor effect in liver cancer, both in vitro and in vivo; therefore, LAP1 may prove to be a potential target in liver CSC-targeted therapy. Keywords: LAP1, liver-enriched activator protein 1, hepatocellular carcinoma, HCC, liver cancer stem cell

For decades, the central nervous system was considered to be an immune privileged organ with limited access to systemic immunity. However, the leptomeninges, the cerebrospinal fluid (CSF)-filled anatomical structure that protects the brain and spinal cord, represent a relatively immune-rich environment. Despite the presence of immune cells, complications in the CSF, such as infectious meningitis and a neurological development of cancer known as leptomeningeal metastasis, are difficult to treat and are frequently fatal. We show that immune cells entering the CSF are held in an ‘idle' state that limits their cytotoxic arsenal and antigen presentation machinery. To understand this underappreciated neuroanatomic niche, we used unique mouse models and rare patient samples to characterize its cellular composition and critical signaling events in health and disease at a single-cell resolution. Revealing the mediators of CSF immune response will allow us to re-evaluate current therapeutic protocols and employ rational combinations with immunotherapies, therefore turning the patient's own immune system into an active weapon against pathogens and cancer. Citation Format: Jan Remsik, Xinran Tong, Ugur Sener, Min Jun Li, Jessica Wilcox, Danielle Isakov, Camille Derderian, Kiana Chabot, Andrea Schietinger, Adrienne Boire. Decoding the immune system response to leptomeningeal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1751.

Objective To investigate the interaction of long non-coding RNA zinc finger antisense 1 (lncRNA ZFAS1) in secondary cerebral edema (CE) and neuron injuries after traumatic brain injury (TBI) in a mouse model. Methods TBI mouse models was established by free-fall strike. Adeno-associated virus-short hairpin-ZFAS1 was administrated into mice via intracerebral injection to downregulate lncRNA ZFAS1. LncRNA ZFAS1 in mouse brain was examined. Neurological severity score (NSS), cerebral water content (CWC) and lesion volume were measured. The number of TUNEL-positive cells in brain tissue was accessed. Bax and cleaved caspase-3 in brain tissues were measured by western blot analysis, and pro-inflammatory factor levels were detected. Results LncRNA ZFAS1 expression was upregulated in mouse brain tissues 3 days after TBI modelling. After the knockdown of lncRNA ZFAS1, NSS, CWC and lesion volume were decreased, apoptotic gene levels were decreased and pro-inflammatory cytokine levels were reduced, suggesting that lncRNA ZFAS1 knockdown could alleviate TBI-induced brain injuries in mice. Conclusion This study demonstrated that silencing lncRNA ZFAS1 inhibited TBI by quenching apoptosis, reducing inflammatory response and improving the recovery of neurological function in TBI mice. LncRNA ZFAS1 might function as a possible curative management in secondary CE and neuron injury in TBI mice.

Background The effectiveness and safety of warfarin use among patients with atrial fibrillation (AF) and reduced kidney function are uncertain. Study Design Community-based retrospective cohort study (May 1, 2003, to March 31, 2012) using province-wide laboratory and administrative data in Alberta, Canada. Setting & Participants 14,892 adults 66 years or older with new AF and a measurement of kidney function. Long-term dialysis patients or kidney transplant recipients were excluded. Predictor Propensity scores were used to construct a matched-pairs cohort of patients with AF who did and did not have a warfarin prescription within a 60-day period surrounding their AF diagnosis. Outcomes Within 1 year of initiating warfarin therapy (or the matched date for nonusers): (1) the composite of all-cause death, ischemic stroke, or transient ischemic attack (also assessed as separate end points) and (2) first hospitalization or emergency department visit for a major bleeding episode defined as an intracranial, upper or lower gastrointestinal, or other bleeding. Measurements Baseline glomerular filtration rate (GFR) was estimated using the CKD-EPI creatinine equation. Patients were matched within estimated GFR (eGFR) categories: ≥90, 60 to 89, 45 to 59, 30 to 44, and Results Across eGFR categories, warfarin therapy initiation was associated with lower risk for the composite outcome compared to nonuse (adjusted HRs [95% CI] for eGFR categories ≥ 90, 60-89, 45-59, 30-44, and Limitations Selection bias. Conclusions Among older adults with AF, warfarin therapy initiation was associated with a significantly lower 1-year risk for the composite outcome across all strata of kidney function. The risk for major bleeding associated with warfarin use was increased only among those with eGFRs of 60 to 89mL/min/1.73m2.

Inflammation in tumor microenvironments is implicated in the pathogenesis of tumor development. In particular, inflammasomes, which modulate innate immune functions, are linked to tumor growth and anticancer responses. However, the role of the NLRC4 inflammasome in gliomas remains unclear. Here, we investigated whether the upregulation of the NLRC4 inflammasome is associated with the clinical prognosis of gliomas. We analyzed the protein expression and localization of NLRC4 in glioma tissues from 11 patients by immunohistochemistry. We examined the interaction between the expression of NLRC4 and clinical prognosis via a Kaplan-Meier survival analysis. The level of NLRC4 protein was increased in brain tissues, specifically, in astrocytes, from glioma patients. NLRC4 expression was associated with a poor prognosis in glioma patients, and the upregulation of NLRC4 in astrocytomas was associated with poor survival. Furthermore, hierarchical clustering of data from the Cancer Genome Atlas dataset showed that NLRC4 was highly expressed in gliomas relative to that in a normal healthy group. Our results suggest that the upregulation of the NLRC4 inflammasome contributes to a poor prognosis for gliomas and presents a potential therapeutic target and diagnostic marker.