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Abstract Backgrounds/Aim Recent studies have shown that the addition of sodium-glucose co-transporter 2 (SGLT2) inhibitors gradually reduces the estimated fluid volume parameters in a broad range of patient populations, suggesting that this mediates the clinical benefits of SGLT2 inhibitors in preventing heart failure. Here, we sought to examine the long-term (24 months) effect of the SGLT2 inhibitor ipragliflozin on the estimated fluid volume parameters in patients with type 2 diabetes mellitus (T2DM). Methods In this prespecified sub-analysis of the PROTECT (Prevention of Atherosclerosis by SGLT2 Inhibitor: Multicenter, Randomized Controlled Study) trial, which was an investigator-initiated, multicenter, prospective, randomized, open-label, clinical trial primarily designed to evaluate the effect of ipragliflozin treatment administered for 24 months on carotid atherosclerosis in patients with T2DM, we evaluated serial changes in estimated plasma volume (ePV, %) calculated using the Straus formula and estimated extracellular volume (eEV, mL) calculated by the body surface area by 24 months following the initiation of 50-mg ipragliflozin once daily and compared them with those following standard care for T2DM (non-SGLT2 inhibitor use). Results This sub-analysis included 464 patients (ipragliflozin, n = 232; control, n = 232), a full analysis set of the PROTECT trial. In an analysis using mixed-effects models for repeated measures, relative to the control group, ipragliflozin significantly reduced ePV by − 10.29% (95% confidence interval [CI] − 12.47% to − 8.11%; P

Abstract Background We assessed the impact of 24 months of treatment with ipragliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on endothelial function in patients with type 2 diabetes as a sub-analysis of the PROTECT study. Methods In the PROTECT study, patients were randomized to receive either standard antihyperglycemic treatment (control group, n = 241 ) or add-on ipragliflozin treatment (ipragliflozin group, n = 241) in a 1:1 ratio. Among the 482 patients in the PROTECT study, flow-mediated vasodilation (FMD) was assessed in 32 patients in the control group and 26 patients in the ipragliflozin group before and after 24 months of treatment. Results HbA1c levels significantly decreased after 24 months of treatment compared to the baseline value in the ipragliflozin group, but not in the control group. However, there was no significant difference between the changes in HbA1c levels in the two groups (7.4 ± 0.8% vs. 7.0 ± 0.9% in the ipragliflozin group and 7.4 ± 0.7% vs. 7.3 ± 0.7% in the control group; P = 0.08). There was no significant difference between FMD values at baseline and after 24 months in both groups (5.2 ± 2.6% vs. 5.2 ± 2.6%, P = 0.98 in the ipragliflozin group; 5.4 ± 2.9% vs. 5.0 ± 3.2%, P = 0.34 in the control group). There was no significant difference in the estimated percentage change in FMD between the two groups (P = 0.77). Conclusions Over a 24-month period, the addition of ipragliflozin to standard therapy in patients with type 2 diabetes did not change endothelial function assessed by FMD in the brachial artery. Trial registration Registration Number for Clinical Trial: jRCT1071220089 ( https://jrct.niph.go.jp/en-latest-detail/jRCT1071220089 ).

Background: Despite the high mortality in patients with pneumonia admitted to an ICU, data on risk factors for death remain limited.Methods: In this secondary analysis of PROTECT (Prophylaxis for Thromboembolism in Critical Care Trial), we focused on the patients admitted to ICU with a primary diagnosis of pneumonia. The primary outcome for this study was 90-day hospital mortality and the secondary outcome was 90-day ICU mortality. Cox regression model was conducted to examine the relationship between baseline and time-dependent variables and hospital and ICU mortality.Results: Six hundred sixty seven patients admitted with pneumonia (43.8 % females) were included in our analysis, with a mean age of 60.7 years and mean APACHE II score of 21.3. During follow-up, 111 patients (16.6 %) died in ICU and in total, 149 (22.3 %) died in hospital. Multivariable analysis demonstrated significant independent risk factors for hospital mortality including male sex (hazard ratio (HR) = 1.5, 95 % confidence interval (CI): 1.1 - 2.2, p-value = 0.021), higher APACHE II score (HR = 1.2, 95 % CI: 1.1 - 1.4, p-value < 0.001 for per-5 point increase), chronic heart failure (HR = 2.9, 95 % CI: 1.6 - 5.4, p-value = 0.001), and dialysis (time-dependent effect: HR = 2.7, 95 % CI: 1.3 - 5.7, p-value = 0.008). Higher APACHE II score (HR = 1.2, 95 % CI: 1.1 - 1.4, p-value = 0.002 for per-5 point increase) and chronic heart failure (HR = 2.6, 95 % CI: 1.3 - 5.0, p-value = 0.004) were significantly related to risk of death in the ICU.Conclusion: In this study using data from a multicenter thromboprophylaxis trial, we found that male sex, higher APACHE II score on admission, chronic heart failure, and dialysis were independently associated with risk of hospital mortality in patients admitted to ICU with pneumonia. While high illness severity score, presence of a serious comorbidity (heart failure) and need for an advanced life support (dialysis) are not unexpected risk factors of mortality, male sex might necessitate further exploration. More studies are warranted to clarify the effect of these risk factors on survival in critically ill patients admitted to ICU with pneumonia.Trial Registration: ClinicalTrials.gov Identifier: NCT00182143 . [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the interobserver reliability of echocardiographic findings of right ventricle (RV) dysfunction for prognosticating normotensive patients with pulmonary embolism (PE).Methods: A central panel of cardiologists evaluated echocardiographic studies of 75 patients included in the PROTECT study for the following signs: RV diameter, RV/left ventricular (LV) diameter ratio, hypokinesis of the RV free wall, and tricuspid plane systolic excursion (TAPSE). Investigators used intraclass correlation to assess agreement between the measurements of the central panel and each of the local cardiologists. Investigators used the single weighted kappa statistic to test for agreement between readers of interpretation of RV enlargement and RV hypokinesis.Results: The two observers had fair agreement (k = 0.45) for RV enlargement assessed by the RV diameter, and good agreement (k = 0.65) for RV enlargement assessed by the RV/LV diameter ratio. The interobserver reliability of the assessment whether hypokinesis of the RV free wall is present was good (к = 0.70), and whether RV dysfunction (assessed by TAPSE measurement) is present was very good (k = 0.86). The intraclass correlation for the RV/LV diameter ratio was fair (0.55; 95% confidence interval [CI], 0.37-0.69), for the RV diameter was good (0.70; 95% CI, 0.56-0.80), and for the TAPSE measurement was very good (0.85; 95% CI, 0.77-0.90). On Bland-Altman analysis, the mean differences for RV diameter, RV/LV diameter ratio and TAPSE measurement were 2.33 (±5.38), 0.06 (±0.23) and 0.08 (±2.20), respectively.Conclusion: TAPSE measurement is the least user dependent and most reproducible echocardiographic finding of RV dysfunction in normotensive patients with PE. [ABSTRACT FROM AUTHOR]

Rationale: Not all patients with acute pulmonary embolism (PE) have a high risk of an adverse short-term outcome., Objectives: This prospective cohort study aimed to develop a multimarker prognostic model that accurately classifies normotensive patients with PE into low and high categories of risk of adverse medical outcomes., Methods: The study enrolled 848 outpatients from the PROTECT (PROgnosTic valuE of Computed Tomography) study (derivation cohort) and 529 patients from the Prognostic Factors for Pulmonary Embolism (PREP) study (validation cohort). Investigators assessed study participants for a 30-day complicated course, defined as death from any cause, hemodynamic collapse, and/or adjudicated recurrent PE., Measurements and Main Results: A complicated course occurred in 63 (7.4%) of the 848 normotensive patients with acute symptomatic PE in the derivation cohort and in 24 patients (4.5%) in the validation cohort. The final model included the simplified Pulmonary Embolism Severity Index, cardiac troponin I, brain natriuretic peptide, and lower limb ultrasound testing. The model performed similarly in the derivation (c-index of 0.75) and validation (c-index of 0.85) cohorts. The combination of the simplified Pulmonary Embolism Severity Index and brain natriuretic peptide testing showed a negative predictive value for a complicated course of 99.1 and 100% in the derivation and validation cohorts, respectively. The combination of all modalities had a positive predictive value for the prediction of a complicated course of 25.8% in the derivation cohort and 21.2% in the validation cohort., Conclusions: For normotensive patients who have acute PE, we derived and validated a multimarker model that predicts all-cause mortality, hemodynamic collapse, and/or recurrent PE within the following 30 days.