The characteristics of patients who were included in the primary analysis, TRENDS study (n = 370).

The characteristics of patients who were included in the primary analysis, TRENDS study (n = 370).</p

Estimated detection rates for daily snapshot monitoring in patients with stroke risk factors.

<p>Estimated detection rates for daily snapshot monitoring in patients with stroke risk factors.</p

Estimated detection rates for daily snapshot monitoring classified based on low/high CHADS₂ score and low/high AT/AF burden (n = 370).

<p>Estimated detection rates for daily snapshot monitoring classified based on low/high CHADS₂ score and low/high AT/AF burden (n = 370).</p

Histogram of the patient’s AT/AF burden (n = 370).

<p>AT/AF burden was defined as the amount of time spent in AT/AF on a given day. Average AT/AF burden per day over the monitoring period (A), maximum daily AT/AF burden, defined as the single day with maximal burden over the monitoring period (B), and the percentage of days over the monitoring period that the patient experienced AT/AF (C) were determined for each of the 370 patients in the primary analysis and are shown as a histogram. Each bar in Fig 1A and 1B indicates the proportion of individuals who were assigned into the corresponding group divided by 1-hour interval of the aggregated AT/AF events among 370 patients. For example, the bar of 6 hours/day in Fig 1A indicates that the proportion of patients with an average AT/AF burden between 5 to 6 hours/day among the 370 patients was 0.5%.</p

Clinicopathological and molecular characteristics among different macroscopic subtypes of CRNs.

<p>*, P values were calculated by Chi-square test or Kruskal-Wallis test. PN, polypoid neoplasm; LST-G, granular type laterally spreading tumor; LST-NG, non-granular type LST; DN, depressed neoplasm; proximal, cecum, ascending and transverse colon; distal, descending and sigmoid colon, and rectum; LGD, low grade dysplasia; HGD, high grade dysplasia; MSI-H, high frequency microsatellite instability; CIMP, CpG island methylator phenotype; Mut+, presence of mutation; Mut-, absence of mutation.</p

Distinct Molecular Features of Different Macroscopic Subtypes of Colorectal Neoplasms

<div><p>Background</p><p>Colorectal adenoma develops into cancer with the accumulation of genetic and epigenetic changes. We studied the underlying molecular and clinicopathological features to better understand the heterogeneity of colorectal neoplasms (CRNs).</p><p>Methods</p><p>We evaluated both genetic (mutations of <i>KRAS</i>, <i>BRAF</i>, <i>TP53</i>, and <i>PIK3CA</i>, and microsatellite instability [MSI]) and epigenetic (methylation status of nine genes or sequences, including the CpG island methylator phenotype [CIMP] markers) alterations in 158 CRNs including 56 polypoid neoplasms (PNs), 25 granular type laterally spreading tumors (LST-Gs), 48 non-granular type LSTs (LST-NGs), 19 depressed neoplasms (DNs) and 10 small flat-elevated neoplasms (S-FNs) on the basis of macroscopic appearance.</p><p>Results</p><p>S-FNs showed few molecular changes except <i>SFRP1</i> methylation. Significant differences in the frequency of <i>KRAS</i> mutations were observed among subtypes (68% for LST-Gs, 36% for PNs, 16% for DNs and 6% for LST-NGs) (P<0.001). By contrast, the frequency of <i>TP53</i> mutation was higher in DNs than PNs or LST-Gs (32% vs. 5% or 0%, respectively) (P<0.007). We also observed significant differences in the frequency of CIMP between LST-Gs and LST-NGs or PNs (32% vs. 6% or 5%, respectively) (P<0.005). Moreover, the methylation level of LINE-1 was significantly lower in DNs or LST-Gs than in PNs (58.3% or 60.5% vs. 63.2%, P<0.05). <i>PIK3CA</i> mutations were detected only in LSTs. Finally, multivariate analyses showed that macroscopic morphologies were significantly associated with an increased risk of molecular changes (PN or LST-G for <i>KRAS</i> mutation, odds ratio [OR] 9.11; LST-NG or DN for <i>TP53</i> mutation, OR 5.30; LST-G for <i>PIK3CA</i> mutation, OR 26.53; LST-G or DN for LINE-1 hypomethylation, OR 3.41).</p><p>Conclusion</p><p>We demonstrated that CRNs could be classified into five macroscopic subtypes according to clinicopathological and molecular differences, suggesting that different mechanisms are involved in the pathogenesis of colorectal tumorigenesis.</p></div

Molecular alterations in relation to clinicopathological findings (multivariate analysis).

<p>*, We used the median of methylation density of LST-G and DNs (59%) as a cut-off value for LINE-1 hypomethylation. CIMP, CpG island methylator phenotype; PN, polypoid neoplasm; LST-G, granular type laterally spreading tumor; LST-NG, non-granular type LST; DN, depressed neoplasm.</p

Macroscopic subtypes in colorectal tumorigenesis.

<p>Precursor lesions can progress to cancer through the acquisition of epigenetic or genetic changes. Tumors from each subtype exhibit different characteristics, including their underlying molecular and genetic defects. However, whether small flat-elevated neoplasms can progress to other subtypes of CRNs remains unknown. PN, Polypoid neoplasm; LST-G, granular type laterally spreading tumor; LST-NG, non-granular type laterally spreading tumor; S-FN, small flat-elevated neoplasm; DN, depressed neoplasm.</p

Clinicopathological features of colorectal neoplasms.

<p>*, all cases were submucosal cancers. Proximal, cecum, ascending and transverse colon; distal, descending and sigmoid colon, and rectum; LGD, low grade dysplasia; HGD, high grade dysplasia; PN, polypoid neoplasm; LST-G, granular type laterally spreading tumor; LST-NG, non-granular type LST; S-FN, small flat-elevated neoplasm; DN, depressed neoplasm; NA, not applicable.</p

Kidney Outcomes Associated With SGLT2 Inhibitors Versus Other Glucose-Lowering Drugs in Real-world Clinical Practice: The Japan Chronic Kidney Disease Database

Objective: Randomized controlled trials have shown kidney protective effects of sodium glucose transporter 2 (SGLT2) inhibitors, and clinical practice databases have suggested that these effects translate to clinical practice. However, long-term efficacy as well as whether the presence or absence of proteinuria and the rate of estimated glomerular filtration rates (eGFR) decline prior to SGLT2 inhibitors initiation modifies treatment efficacy among type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) patients is unknown. Research Design and Methods: Using the Japan Chronic Kidney Disease Database (J-CKD-DB), a nationwide multicenter CKD registry, we developed propensity scores for SGLT2 inhibitor initiation, with 1:1 matching with patients who were initiated on other glucose-lowering drugs. The primary outcome included rate of eGFR decline, and the secondary outcomes included a composite outcome of 50% eGFR decline or end-stage kidney disease. Results: At baseline, mean age at initiation of the SGLT2 inhibitor (n=1,033) or other glucose-lowering drug (n=1,033) was 64.4 years; mean eGFR was 68.1 mL/min per 1.73 m²; and proteinuria was apparent in 578 (28.0%) of included patients. During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs other drugs 0.75 mL/min/1.73 m² per year (0.51 to 1.00). During a mean follow-up of 24 months, 103 composite kidney outcomes occurred: 30 (14 events per 1,000 patient-years) among the SGLT2 inhibitors group and 73 (36 events per 1,000 patient-years) among the other drugs group (hazard ratio 0.40, 95% CI 0.26 to 0.61). The benefit provided by SGLT2 inhibitors was consistent irrespective of proteinuria and rate of eGFR decline before initiating SGLT2 inhibitors (pheterogeneity ≥0.35). Conclusions: The benefits of SGLT2 inhibitors on kidney function as observed in clinical trials translate to patients treated in clinical practice with no evidence that the effects are modified by the underlying rate of kidney function decline or the presence of proteinuria.</p