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ObjectiveEctopic accumulation of cardiac adipose tissue volume (CAT) has been associated with cardiac remodelling and cardiac dysfunction in type 2 diabetes and may be a future therapeutic target. In this substudy from the SIMPLE-trial, we investigated short-term empagliflozin therapy's effects on CAT in patients with type 2 diabetes.Research design and MethodsBetween 4 April 2017 and 11 May 2020, we randomized 90 patients with type 2 diabetes and established or high risk of cardiovascular disease to 25 mg empagliflozin or placebo for 13 weeks. The substudy focused on change in CAT evaluated by images acquired during 82Rubidium-positron emissions tomography/computed tomography. The analysis included 78 patients who had at least one scan. Furthermore, we report on the relation to the concurrent effects on left ventricular mass, end-diastolic volume and end-systolic volume, body composition and glucometabolic status.ResultsMean ± SD baseline CAT was 258.5 ± 117.9 ml. Empagliflozin reduced CAT after 13 weeks by 12.41 ml [95% CI (−23.83 to −0.99), p = .034] as compared with placebo. Similarly, left ventricular mass [−5.16 g, 95% CI (−8.80 to −1.52), p = .006], end-diastolic volume and end-systolic volume decreased with empagliflozin. In addition, significant improvements were observed in body composition, with reduced total fat mass, and in measures of glucose and lipid metabolism. However, no correlation was observed between changes in CAT and changes in cardiac parameters and change in CAT appeared mediated primarily by concurrent change in weight.ConclusionsEmpagliflozin provides an early reduction of CAT; however, no association was observed with concurrent changes in cardiac volumetrics Objective: Ectopic accumulation of cardiac adipose tissue volume (CAT) has been associated with cardiac remodelling and cardiac dysfunction in type 2 diabetes and may be a future therapeutic target. In this substudy from the SIMPLE-trial, we investigated short-term empagliflozin therapy's effects on CAT in patients with type 2 diabetes.Research design and Methods: Between 4 April 2017 and 11 May 2020, we randomized 90 patients with type 2 diabetes and established or high risk of cardiovascular disease to 25 mg empagliflozin or placebo for 13 weeks. The substudy focused on change in CAT evaluated by images acquired during (82)Rubidium-positron emissions tomography/computed tomography. The analysis included 78 patients who had at least one scan. Furthermore, we report on the relation to the concurrent effects on left ventricular mass, end-diastolic volume and end-systolic volume, body composition and glucometabolic status.Results: Mean +/- SD baseline CAT was 258.5 +/- 117.9 ml. Empagliflozin reduced CAT after 13 weeks by 12.41 ml [95% CI (-23.83 to -0.99), p = .034] as compared with placebo. Similarly, left ventricular mass [-5.16 g, 95% CI (-8.80 to -1.52), p = .006], end-diastolic volume and end-systolic volume decreased with empagliflozin. In addition, significant improvements were observed in body composition, with reduced total fat mass, and in measures of glucose and lipid metabolism. However, no correlation was observed between changes in CAT and changes in cardiac parameters and change in CAT appeared mediated primarily by concurrent change in weight.Conclusions: Empagliflozin provides an early reduction of CAT; however, no association was observed with concurrent changes in cardiac volumetrics.

Background Early heart failure prevention is central in patients with type 2 diabetes, and mineralocorticoid receptor antagonists (MRAs) have shown to improve prognosis. We investigated the effect of high-dose MRA, eplerenone, on cardiac function and structure in patients with type 2 diabetes and established or increased risk of cardiovascular disease but without heart failure. Methods In the current randomized, placebo-controlled clinical trial, 140 patients with high-risk type 2 diabetes were randomized to high-dose eplerenone (100–200 mg daily) or placebo as add-on to standard care for 26 weeks. Left ventricular systolic and diastolic function, indexed left ventricular mass (LVMi), and global longitudinal strain (GLS) were assessed using echocardiography at baseline and after 26 weeks of treatment. Results Of the included patients, 138 (99%) had an echocardiography performed at least once. Baseline early diastolic in-flow velocity (E-wave) indexed by mitral annulus velocity (e’) was mean (SD) 11.1 (0.5), with 31% of patients reaching above 12. No effect of treatment on diastolic function was observed measured by E/e’ (0.0, 95%CI [-1.2 to 1.2], P = 0.992) or E/A (-0.1, 95%CI [-0.2 to 0.0], P = 0.191). Mean left ventricular ejection fraction (LVEF) at baseline was 59.0% (8.0). No improvement in systolic function was observed when comparing groups after 26 weeks (LVEF: 0.9, 95%CI [-1.1 to 2.8], P = 0.382; GLS: -0.4%, 95%CI [-1.5 to 0.6], P = 0.422), nor in LVMi (-3.8 g/m2 95%CI [-10.2 to 2.7], P = 0.246). Conclusion In the present echo sub-study, no change in left ventricular function was observed following high-dose MRA therapy in patients with type 2 diabetes when evaluated by conventional echocardiography. Trial registration Date of registration 25/08/2015 (EudraCT number: 2015–002,519-14).

Clinical and animal studies have shown that coexpression of the receptor tyrosine kinases HER2 and epidermal growth factor (EGF) receptor (EGFR) indicates a highly metastatic phenotype of breast cancer. In a cellular model of this phenotype using differential gene expression analysis, we identified TOB1 to be up-regulated depending on EGF stimulation and transduction through phosphorylation of HER2 tyrosine 1248. mRNA expression analysis of breast cancers from a cohort of node-negative patients showed significantly shortened distant metastasis-free survival for patients with high TOB1 expression. In subsequent tissue microarray studies of 725 clinical samples, high HER2 and EGF protein levels were significantly correlated with TOB1 expression in breast cancer, whereas EGFR and EGF levels correlated with TOB1 phosphorylation. We did not observe a correlation between TOB1 expression and cyclin D1, which was previously suggested to mediate the antiproliferative effect of unphosphorylated TOB1. A positive correlation of TOB1 phosphorylation status with proliferation marker Ki67 suggests that elevated TOB1 phosphorylation might abrogate the antiproliferative effect of TOB1 in breast cancer. This suggests a new regulatory role for TOB1 in cancer progression with particular significance in HER2- and/or EGFR-positive breast cancers. [Cancer Res 2009;69(12):5049–56]

Supplementary Tables 1-8 from TOB1 Is Regulated by EGF-Dependent HER2 and EGFR Signaling, Is Highly Phosphorylated, and Indicates Poor Prognosis in Node-Negative Breast Cancer

Daphnia are a keystone species in lentic systems worldwide and an important prey source for planktivorous fishes, such as kokanee (lacustrine Oncorhynchus nerka). Managers have added nutrients, nitrogen (N) and (or) phosphorus (P), in an attempt to improve the growth or carrying capacity for fish by increasing available prey, such as Daphnia. To be successful, this strategy requires that fish growth be prey limited, and prey availability be nutrient limited. In this study, kokanee in Dworshak Reservoir, Idaho fed preferentially on Daphnia ≥ 0.8 mm TL. The biomass of consumable Daphnia decreased with increasing kokanee abundance, indicating top-down control. However, the biomass of consumable Daphnia was greater at any given level of kokanee abundance when N was added to the reservoir, indicating bottom-up control. These results provide an example where Daphnia biomass was simultaneously controlled by both bottom-up and top-down forces, and that N addition alone can be an effective tool for increasing Daphnia biomass.

Objectives This study investigated the impact of the MR antagonist (MRA) eplerenone on LVM in type 2 diabetes patients at high risk for cardiovascular disease (CVD). Background MRA activat...

To investigate the effects of 13 weeks treatment with empagliflozin in patients with high-risk type-2 diabetes mellitus on echocardiographic measures of left ventricular (LV) structure and function compared to placebo. A total of 91 patients were randomized to treatment with empagliflozin (25 mg/day, n = 45) or matching placebo (n = 45) for 13 weeks. Left ventricular (LV) mass, volumes and geometry as well as measures of LV systolic and diastolic function were measured using echocardiography at baseline and follow up. Mean LV mass index (LVMi) was reduced by − 11.5 g/m2 (95% CI − 56.4; 33.4, p = 0.03) with empagliflozin compared to − 1.4 g/m2 (95% CI − 36.5; 33.8, p = 0.63) for placebo. The proportion of patients with LV hypertrophy was reduced by 16.3% (p = 0.04) in the empagliflozin group compared to 1.1% in the placebo group (p = 1.00). The proportion of patients with left atrial volume index > 34 mL/m2 was reduced by 20.0% (p = 0.02) with empagliflozin compared to 9.5% for placebo (p = 0.45) and the E/e′ ratio decreased (∆-0.8 (1.9) vs. ∆0.5 (2.0), p < 0.01). 13 weeks empagliflozin treatment in patients with type-2 diabetes at high CV risk significantly reduced LV mass, improved LV geometry and improved diastolic function compared to placebo.

Blazars research is one of the hot topics of contemporary extra-galactic astrophysics. That is because these sources are the most abundant type of extra-galactic gamma-ray sources and are suspected to play a central role in multi-messenger astrophysics. We have used swift_xrtproc, a tool to carry out an accurate spectral and photometric analysis of the Swift-XRT data of all blazars observed by Swift at least 50 times between December 2004 and the end of 2020. We present a database of X-ray spectra, best-fit parameter values, count-rates and flux estimations in several energy bands of over 31,000 X-ray observations and single snapshots of 65 blazars. The results of the X-ray analysis have been combined with other multi-frequency archival data to assemble the broad-band Spectral Energy Distributions (SEDs) and the long-term light-curves of all sources in the sample. Our study shows that large X-ray luminosity variability on different timescales is present in all objects. Spectral changes are also frequently observed with a "harder-when-brighter" or "softer-when-brighter" behavior depending on the SED type of the blazars. The peak energy of the synchrotron component nu_peak in the SED of HBL blazars, estimated from the log-parabolic shape of their X-ray spectra, also exhibits very large changes in the same source, spanning a range of over two orders of magnitude in Mrk421 and Mrk501, the objects with the best data sets in our sample., Accepted for publication in MNRAS

To investigate the effects of 13 weeks treatment with empagliflozin in patients with high-risk type-2 diabetes mellitus on echocardiographic measures of left ventricular (LV) structure and function compared to placebo. A total of 91 patients were randomized to treatment with empagliflozin (25 mg/day, n = 45) or matching placebo (n = 45) for 13 weeks. Left ventricular (LV) mass, volumes and geometry as well as measures of LV systolic and diastolic function were measured using echocardiography at baseline and follow up. Mean LV mass index (LVMi) was reduced by - 11.5 g/m

Background Sodium–glucose cotransporter 2 inhibitors reduce hospitalizations for heart failure and cardiovascular death, although the underlying mechanisms have not been resolved. The SIMPLE trial (The Effects of Empagliflozin on Myocardial Flow Reserve in Patients With Type 2 Diabetes Mellitus) investigated the effects of empagliflozin on myocardial flow reserve (MFR) reflecting microvascular perfusion, in patients with type 2 diabetes mellitus at high cardiovascular disease risk. Methods and Results We randomized 90 patients to either empagliflozin 25 mg once daily or placebo for 13 weeks, as add‐on to standard therapy. The primary outcome was change in MFR at week 13, quantified by Rubidium‐82 positron emission tomography/computed tomography. The secondary key outcomes were changes in resting rate‐pressure product adjusted MFR, changes to myocardial flow during rest and stress, and reversible cardiac ischemia. Mean baseline MFR was 2.21 (95% CI, 2.08–2.35). There was no change from baseline in MFR at week 13 in either the empagliflozin: 0.01 (95% CI, −0.18 to 0.21) or placebo groups: 0.06 (95% CI, −0.15 to 0.27), with no treatment effect −0.05 (95% CI, −0.33 to 0.23). No effects on the secondary outcome parameters by Rubidium‐82 positron emission tomography/computed tomography was observed. Treatment with empagliflozin reduced hemoglobin A 1c by 0.76% (95% CI, 1.0–0.5; P P Conclusions Empagliflozin did not improve MFR among patients with type 2 diabetes mellitus and high cardiovascular disease risk. The present study does not support that short‐term improvement in MFR explains the reduction in cardiovascular events observed in the outcome trials. Registration URL: https://clinicaltrialsregister.eu/ ; Unique identifier: 2016‐003743‐10.

Purpose Recovery from aphasia after stroke has a decelerating trajectory, with the greatest gains taking place early and the slope of change decreasing over time. Despite its importance, little is known regarding evolution of language function in the early postonset period. The goal of this study was to characterize the dynamics and nature of recovery of language function in the acute and early subacute phases of stroke. Method Twenty-one patients with aphasia were evaluated every 2–3 days for the first 15 days after onset of acute ischemic or hemorrhagic stroke. Language function was assessed at each time point with the Quick Aphasia Battery (Wilson, Eriksson, Schneck, & Lucanie, 2018), which yields an overall summary score and a multidimensional profile of 7 different language domains. Results On a 10-point scale, overall language function improved by a mean of 1.07 points per week, confidence interval [0.46, 1.71], with 19 of 21 patients showing positive changes. The trajectory of recovery was approximately linear over this time period. There was significant variability across patients, and patients with more impaired language function at Day 2 poststroke experienced greater improvements over the subsequent 2 weeks. Patterns of recovery differed across language domains, with consistent improvements in word finding, grammatical construction, repetition, and reading, but less consistent improvements in word comprehension and sentence comprehension. Conclusion Overall language function typically improves substantially and steadily during the first 2 weeks after stroke, driven mostly by recovery of expressive language. Information on the trajectory of early recovery will increase the accuracy of prognoses and establish baseline expectations against which to evaluate the efficacy of interventions. Supplemental Material https://doi.org/10.23641/asha.7811876

Disseminated tumor cells (DTCs) are a subset of circulating tumor cells that migrate to the bone marrow. Colorectal cancer is a heterogeneous disease depending on the site of the primary tumor.We aimed to assess the association between the presence of DTCs in the bone marrow and tumor characteristics as well as long‑term treatment outcomes in patients with left‑sided colorectal cancer.This prospective study included 91 patients with left‑sided colorectal cancer (37 with colon cancer and 54 with rectal cancer) treated between 2007 and 2012 in a single tertiary center. Fifteen patients had stage I cancer; 26, stage II; 26, stage III; and 24, stage IV. Overall survival and cancer relapse rates were compared between patients with different cancer stages and DTC status.Bone marrow DTCs were identified in 42 patients (46.1%). The prevalence of DTCs was not related to tumor infiltration depth, nodal involvement, distant metastasis, tumor stage, or primary tumor site. The 5‑year overall survival rates were 59.5% and 53% in the DTC‑positive and DTC‑negative groups, respectively (P = 0.19). There was a notable trend favoring survival in patients with DTCs with stage II and III disease (both separately and when combined). The number of metachronous distant metastases was significantly lower in DTC‑positive patients.The presence of DTCs in the bone marrow is not associated with primary tumor characteristics and seems to reduce metastasis formation in left‑sided colorectal cancer. There is also a trend for improved overall survival in DTC‑positive patients. These results are intriguing and warrant further confirmation.

INTRODUCTION Disseminated tumor cells (DTCs) are a subset of circulating tumor cells that migrate to the bone marrow. Colorectal cancer is a heterogeneous disease depending on the site of the primary tumor. OBJECTIVES We aimed to assess the association between the presence of DTCs in the bone marrow and tumor characteristics as well as long‑term treatment outcomes in patients with left‑sided colorectal cancer. PATIENTS AND METHODS This prospective study included 91 patients with left‑sided colorectal cancer (37 with colon cancer and 54 with rectal cancer) treated between 2007 and 2012 in a single tertiary center. Fifteen patients had stage I cancer; 26, stage II; 26, stage III; and 24, stage IV. Overall survival and cancer relapse rates were compared between patients with different cancer stages and DTC status. RESULTS Bone marrow DTCs were identified in 42 patients (46.1%). The prevalence of DTCs was not related to tumor infiltration depth, nodal involvement, distant metastasis, tumor stage, or primary tumor site. The 5‑year overall survival rates were 59.5% and 53% in the DTC‑positive and DTC‑negative groups, respectively (P = 0.19). There was a notable trend favoring survival in patients with DTCs with stage II and III disease (both separately and when combined). The number of metachronous distant metastases was significantly lower in DTC‑positive patients. CONCLUSIONS The presence of DTCs in the bone marrow is not associated with primary tumor characteristics and seems to reduce metastasis formation in left‑sided colorectal cancer. There is also a trend for improved overall survival in DTC‑positive patients. These results are intriguing and warrant further confirmation.

Key Clinical Message Hepatosplenic gamma‐delta T‐cell lymphoma with concurrent hemophogocytic lymphohistiocytosis is a rare but well‐recognized clinical scenario, associated with a grim prognosis. Clinicians must be aware of this aggressive type of lymphoma so that a prompt diagnosis can be made with timely initiation of systemic therapy and referral for bone marrow transplant.

As mineralocorticoid receptor antagonists (MRAs) may possess renoprotective effects in type 2 diabetes (T2D), it was decided to investigate the impact of high-dose MRA on prespecified secondary endpoints-namely, change in urinary albumin-creatinine ratio (UACR) and 24-h ambulatory blood pressure-in the MIRAD trial.This was a double-blind clinical trial in which T2D patients at high risk of or with established cardiovascular disease (CVD) were randomized to either high-dose (100-200 mg) eplerenone or a dose-matched placebo as an add-on to background antihypertensive treatment for 26 weeks. Safety was evaluated by the incidence of hyperkalaemia and kidney-related adverse events.A total of 140 patients were enrolled (70 in each group). Baseline UACR was 17 mg/g (geometric mean; 95% CI: 13-22); this decreased by 34% in the eplerenone group compared with the placebo group at week 26 (95% CI: -51% to -12%; P = 0.005). There was no significant decrease in 24-h systolic blood pressure (SBP) due to treatment (-3 mmHg; 95% CI: -6 to 1; P = 0.150). However, the observed change in 24-h SBP correlated with the relative change in UACR in the eplerenone group (r = 0.568, P 0.001). Mean baseline (± SD) estimated glomerular filtration rate (eGFR) was 85 (± 18.6) mL/min/1.73 mThe addition of high-dose eplerenone to T2D patients at high risk of CVD can markedly reduce UACR with an acceptable safety profile.

Wilson SM, Brandt DH, Corsi MP, Dux AM. 2017. Early trophic responses to nutrient addition in Dworshak Reservoir, Idaho. Lake Reserv Manage. 34:58–73. Dworshak Reservoir, Idaho, responded favorably across multiple trophic levels after 4 yr of nutrient (primarily ammonium nitrate) additions. Nitrogen (N) and phosphorus (P) concentrations in the epilimnion did not increase, suggesting rapid biological uptake. Secchi depth was not significantly lower during the treatment period and chlorophyll a concentrations were unchanged. At the lowest trophic level, densities of heterotrophic bacteria increased by 109% and pico-cyanobacteria increased by 60% for the treatment period. While we did not observe a significant increase in the mean biovolume of phytoplankton, the proportion of Dolichospermum, an inedible taxa, in the phytoplankton community declined by 74%, coupled with a 94% increase in the proportion of the phytoplankton biovolume that was edible to zooplankton. The mean density of Daphnia for the treatment period was 70% higher than the untreated period. In the fourth year of treatment, kokanee (Oncorhynchus nerka) biomass increased to 233% of the untreated mean and 143% of the highest untreated estimate. Our observations are consistent with reports from similar projects throughout British Columbia, Alaska, and Scandinavia, which suggests ammonium nitrate enrichment should be further explored as a management strategy for mitigating oligotrophication in N limited waters.

Key Clinical Message Vincristine‐induced vocal cord palsy (VCP) is a rare but critical complication. Prompt recognition of VCP is imperative. Vincristine‐induced VCP is reversible, and a complete remission of a lymphoma is still feasible upon withdrawal of vincristine from the chemotherapeutic regimen early in the course of treatment., Vincristine‐induced vocal cord palsy (VCP) is a rare but critical complication. Prompt recognition of VCP is imperative. Vincristine‐induced VCP is reversible, and a complete remission of a lymphoma is still feasible upon withdrawal of vincristine from the chemotherapeutic regimen early in the course of treatment.