Effects of Triiodothyronine Treatment in an Animal Model of Heart Failure with Preserved Ejection Fraction.

Background: Low levels of triiodothyronine (T3) are common in patients with heart failure (HF). Our aim was to evaluate the effects of supplementation with low and replacement doses of T3 in an animal model of HF with preserved ejection fraction (HFpEF). Methods: We evaluated four groups: ZSF1 Lean (n = 8, Lean-Ctrl), ZSF1 Obese (rat model of metabolic-induced HFpEF, n = 13, HFpEF), ZSF1 Obese treated with a replacement dose of T3 (n = 8, HFpEF-T3high), and ZSF1 Obese treated with a low-dose of T3 (n = 8, HFpEF-T3low). T3 was administered in drinking water from weeks 13 to 24. The animals underwent anthropometric and metabolic assessments, echocardiography, and peak effort testing with maximum O2 consumption (VO2max) determination at 22 weeks, and a terminal hemodynamic evaluation at 24 weeks. Afterwhile myocardial samples were collected for single cardiomyocyte evaluation and molecular studies. Results: HFpEF animals showed lower serum and myocardial thyroid hormone levels than Lean-Ctrl. Treatment with T3 did not normalize serum T3 levels, but increased myocardial T3 levels to normal levels in the HFpEF-T3high group. Body weight was significantly decreased in both the T3-treated groups, comparing with HFpEF. An improvement in glucose metabolism was observed only in HFpEF-T3high. Both the treated groups had improved diastolic and systolic function in vivo, as well as improved Ca2+ transients and sarcomere shortening and relaxation in vitro. Comparing with HFpEF animals, HFpEF-T3high had increased heart rate and a higher rate of premature ventricular contractions. Animals treated with T3 had higher myocardial expression of calcium transporter ryanodine receptor 2 (RYR2) and α-myosin heavy chain (MHC), with a lower expression of ß-MHC. VO2max was not influenced by treatment with T3. Myocardial fibrosis was reduced in both the treated groups. Three animals died in the HFpEF-T3high group. Conclusions: Treatment with T3 was shown to improve metabolic profile, myocardial calcium handling, and cardiac function. While the low dose was well-tolerated and safe, the replacement dose was associated with increased heart rate, and increased risk of arrhythmias and sudden death. Modulation of thyroid hormones may be a potential therapeutic target in HFpEF; however, it is important to take into account the narrow therapeutic window of T3 in this condition.

Brown Algae Fucus vesiculosus in Pasta: Effects on Textural Quality, Cooking Properties, and Sensorial Traits.

Fucus vesiculosus is a brown seaweed rich in iodine, fucoxanthin, and phlorotannins, all known to be bioactive compounds associated with health-promoting events. The enrichment of a staple food such as pasta with seaweed flour, could convey health benefits without changing eating habits. In this work, F. vesiculosus flour (FVF) was incorporated into durum wheat pasta at 1, 5.5, and 10% gradient levels. The pasta enriched with FVF needed additional water during dough formation and required more cooking time, resulting in higher weight gain but also increased cooking loss (observed with 5.5 and 10%). The fracturability of raw pasta decreased for all the FVF pasta, though the cooked firmness and hardness were only affected with the inclusion of 10% FVF. The substitution of wheat semolina with FVF at a 10% level caused an increase in the pasta's fiber content, which resulted in a more discontinuous protein-matrix structure, as observed at the microscopic level. Untrained consumers were very positive about the overall sensory traits of the pasta with low supplementation levels (1 and 5.5%). About 72% of panelists selected the 1% FVF pasta as their favorite sample. The utilization of FVF in pasta should be targeted at low inclusion levels to cope with the expected texture quality and prevent the impairment of the sensory traits.

Evaluating the Optimal Sequence of Treatment With EGFR Inhibitors and Bevacizumab in RAS Wild-Type Metastatic Colorectal Cancer.

Background Epithelial growth factor receptor inhibitors (EGFRi) and bevacizumab are the two main target therapies available for first-line treatment of RAS wild-type (wt) metastatic colorectal cancer (mCRC). However, the optimal sequencing of these agents remains unclear. In this study, we aimed to evaluate the optimal sequence with EGFRi and bevacizumab in first- and second-line treatment. Methods This was a retrospective cohort study with RAS wt mCRC patients identified by extended RAS analysis between 2013 and 2020 at a comprehensive cancer center. All patients had to be treated with a sequence of systemic treatment that included an EGFRi and bevacizumab in first and second line, in either order. Two groups were defined according to treatment sequence: first-line EGFRi followed by second-line bevacizumab (cohort A) or the reverse sequence (cohort B). Primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival with first-line treatment (PFS1), progression-free survival with second-line treatment (PFS2), objective response rate (ORR), and serious adverse events (grade ≥ 3). Survival was estimated using the Kaplan-Meier method, and survival differences between groups were compared using the log-rank test. Univariate analyses were performed using Cox proportional hazard model. Results A total of 124 patients were included (93 in cohort A and 31 in cohort B). There were no statistical significant differences in median OS (A: 34.9 months vs B: 29.2 months; p=0.590), PFS1 (A: 13.1 months vs B: 8.2 months; p=0.600), and PFS2 (A: 7.4 months vs B: 5.5 months; p=0.110) between groups. No significant differences were also found between treatment sequences in subgroups defined by age, gender, primary tumor location, sidedness, timing of metastasis, number of metastatic sites, multimodal therapy, primary tumor resection, and first-line chemotherapy backbone. ORR was significantly higher with first-line treatment with EGFRi (A: 55.9% vs B: 22.6%; p=0.001). At the final follow-up, the proportion of patients with SAEs was similar between treatment sequences (p=0.827). Discussion Our study showed no impact of the treatment sequence with EGFRi and bevacizumab in the survival of RAS wt mCRC. However, patients treated with first-line EGFRi had significantly higher response rates, thus favoring its use in patients with symptomatic tumors and borderline resectable metastasis. Prospective trials are warranted to define the optimal sequence of treatment in RAS wt mCRC patients.

Trends in the utilisation of COPD therapeutic regimens before and after the introduction of LAMA/LABA combination products: A population-based study.

INTRODUCTION: Long-acting muscarinic antagonist/long-acting beta agonist (LAMA/LABA) combination products have recently been introduced. We sought to describe the impact of these products on patterns of chronic obstructive pulmonary disease (COPD) therapy. MATERIALS AND METHODS: We used administrative healthcare data from Ontario, Canada, to identify all residents aged ≥ 65 years who were dispensed a product to treat COPD at least once between January 2010 and May 2016, and to calculate the monthly prevalence of use of 11 mutually exclusive therapeutic regimens. We also compared the characteristics of new users of LAMA/LABA and LAMA + LABA regimens. RESULTS: Overall use of any COPD regimen remained stable in the year following the formulary listing of LAMA/LABA combination products in May 2015, as did the use of LABA/ICS (most commonly-used regimen). Use of LAMA/LABA and LAMA/LABA + ICS (inhaled corticosteroid) regimens rose rapidly to 283 and 56 users per 100,000 population, respectively, while concurrent falls were seen for LAMA + LABA/ICS (2047 to 1944), LAMA + LABA + ICS (30-19), and LAMA + LABA (103-63). LAMA and LABA monotherapy use declined (1764 to 1669 and 57 to 51, respectively). New users of LAMA/LABA were more likely to be male, urban-dwelling, and to have transitioned from LABA/ICS therapy than new users of LAMA + LABA, and less likely to have transitioned from LAMA or LABA monotherapy, or LAMA + ICS. They were also more likely to have visited a respirologist, and less likely to have been hospitalised, at least once in the preceding 180 days. CONCLUSIONS: The introduction of LAMA/LABA combination products led to population-level changes in regimens used for COPD therapy, but no overall increase in long-acting therapy use. New users of LAMA/LABA and LAMA + LABA regimens transitioned to dual LAMA and LABA therapy through different treatment pathways.