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BACKGROUND: Ferritin is commonly used to evaluate iron stores and guide therapeutic decisions regarding intravenous iron supplementation. However, in the context of AHF, inflammation-driven upregulation of ferritin might disrupt its correlation with iron stores, restricting iron bioavailability and potentially amplifying the inflammatory response. AIM: This study aims to assess the clinical and prognostic associations of ferritin levels in an AHF cohort and to determine whether the prognostic value of ferritin is influenced by the presence of infection, inflammatory activation, and other markers of iron deficiency. METHODS: The association between ferritin and clinical outcomes (180 days) in AHF was evaluated in a cohort of 526 patients from the EDIFICA registry. RESULTS: The median ferritin plasma concentration at admission was 180 pg/mL. Patients with higher ferritin levels at admission were predominantly men, exhibiting a high prevalence of chronic kidney disease and alcohol consumption, and presenting with lower blood pressure and a higher incidence of clinical infection. Higher ferritin levels were associated with increased risk of the composite of heart failure hospitalization or cardiovascular death (Tertile 2: HR 1.75; 95% CI 1.10-2.79; p = 0.017; Tertile 3: HR 1.79; 95% CI 1.08-2.97; p = 0.025), independently of classical HF prognostic factors, inflammatory and iron-related markers. No significant associations were found between admission serum iron or transferrin saturation tertiles, iron status categories, or guideline-defined iron deficiency (ID) criteria and the primary composite outcome. However, at discharge, patients who met the criteria for defective iron utilization, low iron storage, or guideline-defined ID had a lower risk of the composite endpoint compared to those with normal iron utilization or who did not meet the guideline-defined ID criteria, respectively. CONCLUSIONS: Elevated ferritin levels are independently associated with poor prognosis in AHF. Low ferritin levels are associated with a favorable outcome and do not carry significant value in identifying ID in this population.

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Backgroud: This study investigates the potential of vasodilator drugs as additive therapy in the treatment of urological cancers, particularly in combination with the antineoplastic agent 5-fluorouracil (5-FU). Methods: The study evaluated the cytotoxic effects of sildenafil, tezosentan and levosimendan alone and in combination with 5-FU on urological cancer cell lines. The assessment included MTT assays, colony formation assays and wound healing assays to determine cell viability, proliferative capacity, and migratory behavior, respectively. Results: Sildenafil and tezosentan showed limited cytotoxic effects, while levosimendan demonstrated moderate anticancer activity. The combination of levosimendan and 5-FU exhibited an additive interaction, enhancing cytotoxicity against cancer cells while sparing normal cells. Levosimendan also inhibited cell migration and proliferation, potentially through mechanisms involving the modulation of cAMP levels and nitric oxide production. Conclusions: The findings suggest that levosimendan can be used in conjunction with 5-FU to reduce the required dose of 5-FU, thereby minimizing side effects without compromising therapeutic efficacy. This study offers a new perspective for enhancing therapeutic outcomes in patients with urological cancers.

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BACKGROUND: Despite the increasing interest in the study of the endogenous relaxin system in heart failure (HF), its role as a prognostic marker in acute HF remains unclear. We aimed to evaluate the association of relaxin-2 circulating levels with 6 months' mortality in acute HF. METHODS: We evaluated relaxin-2 serum levels at admission in a cohort of patients with acute HF (n = 202) using an enzyme immunoassay. The ability of relaxin-2 to predict all-cause death (primary outcome) and HF-specific death (secondary outcome) at 6 months was assessed using Cox-regression analysis. RESULTS: The median age was 79 (70-85) years old, 44% of the patients were male, and 43% had preserved ejection fraction (≥50%). Median serum relaxin-2 level was 25 pg/mL. Patients with higher relaxin-2 levels had more peripheral oedemas, higher sodium retention score, higher pulmonary artery pressures, higher prevalence of right ventricle dysfunction and lower inferior vena cava collapse at inspiration. Conversely, there was no association with left chambers parameters or with B-type natriuretic peptide (BNP). Higher relaxin-2 concentrations were associated with a higher risk of all-cause death [HR 1.15; 95%CI 1.01,1.30; P = 0.030] and HF-specific death [HR 1.21; 95% CI 1.03-1.42; P = 0.018], after adjustment for classical prognostic factors such as age, sex and BNP. CONCLUSIONS: In our acute HF population, relaxin-2 circulating levels were associated with clinical and echocardiographic markers of systemic congestion and with 6-months' mortality, independently of BNP. These results lay the groundwork for future investigations on the potential of relaxin-2 as an auxiliary biomarker in HF.

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BACKGROUND: Heart failure (HF) patients often experience poor health-related quality-of-life (HR-QoL). The Kansas City Cardiomyopathy Questionnaire (KCCQ) is frequently used for assessing HR-QoL in HF. Whether KCCQ scores vary in a clinical meaningful manner according to the setting (home vs office) where patients respond to the questionnaire is currently unknown. AIMS: Assess the differences in the responses to KCCQ-23 questionnaire when completed at home or office. METHODS: Randomized parallel-group study, including patients with HF with reduced ejection fraction (HFrEF). Primary outcome was home vs office comparison of overall summary score (KCCQ-OSS). Main secondary outcomes were clinical summary score (KCCQ-CSS) and total symptom score (KCCQ-TSS). RESULTS: A total of 100 patients were included in the study: 50 home vs 50 office. Mean age was 71 yrs. Most baseline characteristics were well balanced between groups, except male sex, MRA use, and prior HF hospitalizations which were more frequent in the home group. No statistically-significant between-group differences were found regarding KCCQ-OSS (median [percentile25-75]) scores: home 69.1 (42.0-86.5) vs office 63.1 (44.3-82.3) points, P-value = 0.59, or main secondary outcomes: KCCQ-CSS home 62.2 (46.5-79.9) vs office 68.1 (51.9-79.2) points, P-value = 0.69, and KCCQ-TSS home 84.7 (59.7-97.2) vs office 76.4 (66.7-94.4) points, P-value = 0.85. Results remained similar after adjustment for differences in baseline characteristics and using non-parametric regressions. CONCLUSIONS: No major differences were found in KCCQ-23 scores regardless of whether the questionnaire was completed at home or office. These findings can be useful to make HR-QoL more accessible, allowing patients to respond at home using email or cell-phone applications.

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BACKGROUND: Dipeptidyl peptidase 3 (DPP3) is a ubiquitous cytosolic enzyme released into the bloodstream after tissue injury, that can degrade angiotensin II. High concentrations of circulating DPP3 (cDPP3) have been associated with worse outcomes during sepsis. The aim of this study was to assess the effect of Procizumab (PCZ), a monoclonal antibody that neutralizes cDPP3, in an experimental model of septic shock. METHODS: In this randomized, open-label, controlled study, 16 anesthetized and mechanically ventilated pigs with peritonitis were randomized to receive PCZ or standard treatment when the mean arterial pressure (MAP) dropped below 50 mmHg. Resuscitation with fluids, antimicrobial therapy, peritoneal lavage, and norepinephrine was initiated one hour later to maintain MAP between 65-75 mmHg for 12 h. Hemodynamic variables, tissue oxygenation indices, and measures of organ failure and myocardial injury were collected. Organ blood flow was assessed using isotopic assessment (99mtechnetium albumin). cDPP3 activity, equilibrium analysis of the renin-angiotensin system and circulating catecholamines were measured. Tissue mRNA expression of interleukin-6 and downregulation of adrenergic and angiotensin receptors were assessed on vascular and myocardial samples. RESULTS: PCZ-treated animals had reduced cDPP3 levels and required less norepinephrine and fluid than septic control animals for similar organ perfusion and regional blood flow. PCZ-treated animals had less myocardial injury, and higher PaO2/FiO2 ratios. PCZ was associated with lower circulating catecholamine levels; higher circulating angiotensin II and higher angiotensin II receptor type 1 myocardial protein expression, and with lower myocardial and radial artery mRNA interleukin-6 expression. CONCLUSIONS: In an experimental model of septic shock, PCZ administration was associated with reduced fluid and catecholamine requirements, less myocardial injury and cardiovascular inflammation, along with preserved angiotensin II signaling.

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The growing disparity between the demand for transplants and the available donor supply, coupled with an aging donor population and increasing prevalence of chronic diseases, highlights the urgent need for the development of platforms enabling reconditioning, repair, and regeneration of deceased donor organs. This necessitates the ability to preserve metabolically active kidneys ex vivo for days. However, current kidney normothermic machine perfusion (NMP) approaches allow metabolic preservation only for hours. Here we show that human kidneys discarded for transplantation can be preserved in a metabolically active state up to 4 days when perfused with a cell-free perfusate supplemented with TCA cycle intermediates at subnormothermia (25 °C). Using spatially resolved isotope tracing we demonstrate preserved metabolic fluxes in the kidney microenvironment up to Day 4 of perfusion. Beyond Day 4, significant changes were observed in renal cell populations through spatial lipidomics, and increases in injury markers such as LDH, NGAL and oxidized lipids. Finally, we demonstrate that perfused kidneys maintain functional parameters up to Day 4. Collectively, these findings provide evidence that this approach enables metabolic and functional preservation of human kidneys over multiple days, establishing a solid foundation for future clinical investigations.

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Background: Pancreas transplant volumes are limited because of poor utilization of "extended criteria grafts." Prolonged cold ischemia is a risk factor associated with poor allograft survival. We aimed to establish the feasibility of transplantation using grafts subjected to prolonged cold ischemia and determine whether these grafts could be optimized using normothermic ex vivo perfusion (NEVP) in a porcine model. Methods: The study population consisted of 35 to 40 kg male Yorkshire pigs in an allotransplantation model with a 3-d survival plan for recipients. Control grafts were subjected to cold storage (CS) in a University of Wisconsin solution for 21 to 24 h (n = 6), whereas the test group received an additional 3 h NEVP after CS of 21 h (n = 5). Results: The 3-d survival was 60% in the NEVP arm versus 0% in the control arm (P = 0.008; log rank). Graft parenchyma was 60% to 70% preserved in the NEVP arm at necropsy on gross appearance. In addition, the islet function was well preserved, and both the pancreas (including the islets) and the duodenal morphology were maintained histologically. The intravenous glucose tolerance test on the day of euthanasia was in the normoglycemic range for 80% of cases in the NEVP arm. Conclusions: Optimization of pancreas grafts exposed to extended CS with NEVP seems promising at rescuing and reanimating these grafts for transplantation, resulting in significantly improved survival in a porcine pancreas transplant model.

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AIMS: Lower respiratory tract infections (LRTI) are common worldwide. Patients with heart failure and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) have a high risk of developing LRTI. Prior studies were able to show that sodium-glucose cotransporter 2 inhibitors may reduce the incidence of LRTI in patients with type 2 diabetes. The aim of this study was to evaluate patient characteristics and prognosis according to LRTI status and to assess the effect of empagliflozin on LRTI in 5988 patients with HFmrEF/HFpEF enrolled in the EMPEROR-Preserved trial randomized to either empagliflozin or placebo over a median follow-up of 26 months. METHODS AND RESULTS: Time-updated models were used to study the mortality risk after a LRTI. Cox regression was used to study the effect of empagliflozin on incident LRTI. Throughout the follow-up, 699 of 5988 (11.7%) patients developed LRTI: these were older, were more frequently hospitalized within the previous year, had type 2 diabetes, chronic kidney disease, and had higher N-terminal pro-B-type natriuretic peptide levels than patients without incident LRTI. Patients who developed LRTI had a 2.7-fold higher risk of subsequent mortality compared to patients without LRTI. The incidence of LRTI was 5.2 (95% confidence interval [CI] 4.6-5.8) events per 100 person-years in the empagliflozin group and 6.2 (95% CI 5.6-6.9) events per 100 person-years in the placebo group (hazard ratio 0.83, 95% CI 0.71-0.96, p = 0.014). The total number of LRTI events was reduced in the empagliflozin group (incidence rate ratio 0.80, 95% CI 0.68-0.94, p = 0.008). No effect of empagliflozin was observed on COVID-19 incidence. CONCLUSION: In EMPEROR-Preserved, LRTI was frequent and associated with a poor prognosis. Empagliflozin was associated with a reduced risk of LRTI compared to placebo.

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BACKGROUND AND AIMS: Inflammation is a risk factor for major adverse cardiovascular events (MACE). Elevated levels of both high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL6) have been associated with MACE. However, few studies have compared IL6 to hsCRP for cardiovascular risk assessment. Using the MESA (Multi-Ethnic Study of Atherosclerosis) study cohort, we aim to compare IL6 to hsCRP. METHODS: We divided IL6 and hsCRP by their median values and created 4 groups i.e., low-low, high-low, low-high and high-high. The median follow-up was 14 years. RESULTS: 6614 (97 %) participants had complete baseline IL6 and hsCRP data. The correlation between hsCRP and IL6 was modest (Rho = 0.53). IL6 ≥1.2 pg/mL (median) was present in 3309 participants, and hsCRP ≥1.9 mg/L (median) was present in 3339 participants. Compared to participants with low IL6 and low hsCRP, those with high IL6 and high hsCRP were older (64 vs. 60 years), more frequently women (63 % vs. 45 %), and with more cardiovascular co-morbidities. hsCRP outcome associations lost statistical significance when adjusting for IL6: MACE HR (95 %CI) 1.06 (0.93-1.20), p =0.39, whereas IL6 associations remained significant after adjusting for hsCRP: HR (95 %CI) 1.44 (1.25-1.64), p <0.001. The C-index of Framingham score for did not improve with hsCRP but improved with IL6. Compared to participants with low IL6 and low hsCRP, those with high IL6, regardless of hsCRP, experienced an increased risk of MACE, heart failure and mortality. CONCLUSIONS: In a diverse and asymptomatic population, IL6 showed a stronger association with atherosclerotic, heart failure and fatal outcomes than hsCRP.

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BACKGROUND: There is uncertainty in the management of cancer-associated isolated splanchnic vein thrombosis (SpVT). OBJECTIVES: To describe the natural history of SpVT by cancer type and thrombus composition and to review anticoagulation (AC) practices and associated rates of usual-site venous thromboembolism (VTE), major and clinically relevant nonmajor bleeding (MB/CRNMB), recanalization/progression, and mortality. METHODS: We performed a retrospective cohort study in patients with SpVT at 2 cancer care centers in Houston, Texas. We estimated the incidence of usual-site VTE and MB/CRNMB at 6 months using competing risk methods and examined venous patency in a subset of patients with repeat imaging. We assessed associations with mortality using Cox regression. RESULTS: Among 15 342 patients with an incident cancer diagnosis from 2011 to 2020, we identified 298 with isolated SpVT. Patients with hepatocellular carcinoma (HCC) and SpVT (n = 146) had the highest disease prevalence (20%), lowest rate of AC treatment (2%), and similar rate of usual-site VTE (4.2%) vs those without SpVT (5.2%) at 6 months, though tumor thrombus vs bland was associated with worse overall survival. In patients with non-HCC bland SpVT (n = 114), AC (n = 37) was more common in those with non-upper gastrointestinal cancers and fewer comorbidities. AC was associated with more recanalization (44% vs 15%, P = .041) but no differences in usual-site VTE, MB/CRNMB, or mortality at 6 months. CONCLUSION: Cancer-associated isolated SpVT is a common but heterogeneous thrombotic disease that is treated differently from usual-site VTE. Tumor thrombus is a negative prognostic factor. Initiation of AC in bland thrombi requires judicious consideration of thrombotic and bleeding risk.

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Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by impaired cardiovascular reserve in which therapeutic options are scarce. Our aim was to evaluate the inodilator levosimendan in the ZSF1 obese rat model of HFpEF. Twenty-week-old male Wistar-Kyoto (WKY), ZSF1 lean (ZSF1 Ln) and ZSF1 obese rats chronically treated for 6-weeks with either levosimendan (1 mg/kg/day, ZSF1 Ob + Levo) or vehicle (ZSF1 Ob + Veh) underwent peak-effort testing, pressure-volume (PV) haemodynamic evaluation and echocardiography (n = 7 each). Samples were collected for histology and western blotting. In obese rats, skinned and intact left ventricular (LV) cardiomyocytes underwent in vitro functional evaluation. Seven additional ZSF1 obese rats underwent PV evaluation to assess acute levosimendan effects (10 µg/kg + 0.1 µg/kg/min). ZSF1 Ob + Veh presented all hallmarks of HFpEF, namely effort intolerance, elevated end-diastolic pressures and reduced diastolic compliance as well as increased LV mass and left atrial area, cardiomyocyte hypertrophy and increased interstitial fibrosis. Levosimendan decreased systemic arterial pressures, raised cardiac index, and enhanced LV relaxation and diastolic compliance in both acute and chronic experiments. ZSF1 Ob + Levo showed pronounced attenuation of hypertrophy and interstitial fibrosis alongside increased effort tolerance (endured workload raised 38 %) and maximum O2 consumption. Skinned cardiomyocytes from ZSF 1 Ob + Levo showed a downward shift in sarcomere length-passive tension relationship and intact cardiomyocytes showed decreased diastolic Ca2+ levels and enhanced Ca2+ sensitivity. On molecular grounds, levosimendan enhanced phosphorylation of phospholamban and mammalian target of rapamycin. The observed effects encourage future clinical trials with levosimendan in a broad population of HFpEF patients.

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[This corrects the article DOI: 10.3389/fcell.2021.624601.].

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BACKGROUND: Extubation during extracorporeal oxygenation (ECMO) in severe acute respiratory distress syndrome (ARDS) has not been well studied. Despite the potential benefits of this strategy, weaning from ECMO before liberation from invasive mechanical ventilation remains the most frequent approach. Our aim was to evaluate the safety and feasibility of a standardized approach for extubation during ECMO in patients with severe ARDS. RESULTS: We conducted a prospective observational study to assess the safety and feasibility of a standardized approach for extubation during ECMO in severe ARDS among 254 adult patients across 4 intensive care units (ICU) from 2 tertiary ECMO centers over 6 years. This consisted of a daily assessment of clinical and gas exchange criteria based on an Extracorporeal Life Support Organization guideline, with extubation during ECMO after validation by a dedicated intensive care medicine specialist. Fifty-four (21%) patients were extubated during ECMO, 167 (66%) did not reach the clinical criteria, and in 33 (13%) patients, gas exchange precluded extubation during ECMO. At ECMO initiation, there were fewer extrapulmonary organ dysfunctions (lower SOFA score [OR, 0.88; 95% CI, 0.79-0.98; P = .02] with similar PaO2/FiO2) when compared with patients not extubated during ECMO. Extubation during ECMO associated with shorter duration of invasive mechanical ventilation (7 (4-18) vs. 32 (18-54) days; P < .01) and of ECMO (12 (7-25) vs. 19 (10-41) days; P = .01). This was accompanied by a lower incidence of hemorrhagic shock (2 vs. 11%; P = .05), but more cannula-associated deep vein thrombosis (49 vs. 31%; P = .02) and failed extubation (20 vs. 6%; P < .01). There were no increased major adverse events. Extubation during ECMO is associated with a lower risk of all-cause death, independently of measured confounding (adjusted logistic regression OR 0.23; 95% confidence interval 0.08-0.69, P = .008). CONCLUSIONS: A standardized approach was safe and feasible allowing extubation during ECMO in 21% of patients with severe ARDS, selecting patients who will have a shorter duration of invasive mechanical ventilation, ECMO course, and ICU stay, as well as fewer infectious complications, and high hospital survival.

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Heart failure with preserved ejection fraction (HFpEF) represents a global health challenge, with limited therapies proven to enhance patient outcomes. This makes the elucidation of disease mechanisms and the identification of novel potential therapeutic targets a priority. Here, we performed RNA sequencing on ventricular myocardial biopsies from patients with HFpEF, prospecting to discover distinctive transcriptomic signatures. A total of 306 differentially expressed mRNAs (DEG) and 152 differentially expressed microRNAs (DEM) were identified and enriched in several biological processes involved in HF. Moreover, by integrating mRNA and microRNA expression data, we identified five potentially novel miRNA-mRNA relationships in HFpEF: the upregulated hsa-miR-25-3p, hsa-miR-26a-5p, and has-miR4429, targeting HAPLN1; and NPPB mRNA, targeted by hsa-miR-26a-5p and miR-140-3p. Exploring the predicted miRNA-mRNA interactions experimentally, we demonstrated that overexpression of the distinct miRNAs leads to the downregulation of their target genes. Interestingly, we also observed that microRNA signatures display a higher discriminative power to distinguish HFpEF sub-groups over mRNA signatures. Our results offer new mechanistic clues, which can potentially translate into new HFpEF therapies.

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AIMS: Intravenous (IV) iron increases haemoglobin/haematocrit and improves outcomes in patients with heart failure with reduced ejection fraction (HFrEF) and iron deficiency. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) also increase haemoglobin/haematocrit and improve outcomes in heart failure by mechanisms linked to nutrient deprivation signalling and reduction of inflammation and oxidative stress. The effect of IV iron among patients using SGLT2i has not yet been studied. The aim of this study was to evaluate the changes in haemoglobin, haematocrit, and iron biomarkers in HFrEF patients treated with IV iron with and without background SGLT2i treatment. Secondary outcomes included changes in natriuretic peptides, kidney function and heart failure-associated outcomes. METHODS AND RESULTS: Retrospective, single-centre analysis of HFrEF patients with iron deficiency treated with IV iron using (n = 60) and not using (n = 60) SGLT2i, matched for age and sex. Mean age was 73 ± 12 years, 48% were men, with more than 65% of patients having chronic kidney disease and anaemia. After adjustment for all baseline differences, SGLT2i users experienced a greater increase in haemoglobin and haematocrit compared to SGLT2i non-users: haemoglobin +0.57 g/dl (95% confidence interval [CI] 0.04-1.10, p = 0.036) and haematocrit +1.64% (95% CI 0.18-3.11, p = 0.029). No significant differences were noted for iron biomarkers or any of the secondary outcomes. CONCLUSION: Combined treatment with IV iron and background SGLT2i was associated with a greater increase in haemoglobin and haematocrit than IV iron without background SGLT2i. These results suggest that in HFrEF patients treated with IV iron, SGLT2i may increase the erythropoietic response. Further studies are needed to ascertain the potential benefit or harm of combining these two treatments in heart failure patients.

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BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors and GLP-1 receptor agonists (GLP-1 RAs) reduce adverse cardiovascular outcomes in type 2 diabetes (T2D). However, the efficacy of combination therapy is unclear. OBJECTIVES: The aim of this study was to evaluate the effects of GLP-1 RAs on cardiovascular outcomes in patients with T2D treated with or without SGLT2 inhibitors. METHODS: Post hoc analysis of Harmony Outcomes (Albiglutide and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Cardiovascular Disease) evaluating the effect of albiglutide in T2D with cardiovascular disease by background SGLT2 inhibitor use. Additionally, a trial-level meta-analysis of Harmony Outcomes and AMPLITUDE-O (Effect of Efpeglenatide on Cardiovascular Outcomes), which evaluated T2D with cardiovascular or renal disease, was performed, combining the treatment effect estimates according to SGLT2 inhibitor use. RESULTS: Of the 9,462 participants in Harmony Outcomes, 575 (6.1%) were treated with SGLT2 inhibitors at baseline. The effect of albiglutide on reducing the composite of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular events) was consistent with or without SGLT2 inhibitors (P interaction = 0.70). The effect of albiglutide on secondary outcomes and adverse events was not modified by SGLT2 inhibitors. A meta-analysis of Harmony Outcomes and AMPLITUDE-O included 13,538 patients, of whom 1,193 (8.8%) used SGLT2 inhibitors. Compared to placebo, GLP1-RAs reduced major adverse cardiovascular events without effect modification by SGLT2 inhibitor use (HR: 0.77; 95% CI: 0.68-0.87 without SGLT2 inhibitors; and HR: 0.78; 95% CI: 0.49-1.24 with SGLT2 inhibitors) (P for interaction = 0.95) and reduced heart failure hospitalization (HR: 0.72; 95% CI: 0.55-0.92 vs HR: 0.34; 95% CI: 0.12-0.96) (P for interaction = 0.18). CONCLUSIONS: In patients with T2D and cardiovascular disease, GLP-1 RAs reduced cardiovascular events independently of SGLT2 inhibitor use. These findings suggest that the combination of GLP-1 RAs with SGLT2 inhibitors may further reduce cardiovascular risk. Clinical trials with combination therapy are needed.

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Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been used to reduce body weight in overweight or people with obesity and to improve glycemic control and cardiovascular outcomes among people with type 2 diabetes (T2D) and a high cardiovascular risk. However, the effects of GLP-1 RAs may be modified by the presence of heart failure (HF). In this review, we summarize the evidence for the use of GLP-1 RA across a patient's risk with a particular focus on HF. After a careful review of the literature, we challenge the current views about the use of GLP-1 RAs and suggest performing active HF screening (with directed clinical history, physical examination, an echocardiogram, and natriuretic peptides) before initiating a GLP-1 RA. After HF screening, we suggest GLP-1 RA treatment decisions as follows: (1) in people with T2D without HF, GLP-1 RAs should be used for reducing the risk of myocardial infarction and stroke, with a possible effect to reduce the risk of HF hospitalizations; (2) in patients with HF and preserved ejection fraction, GLP-1 RAs do not reduce HF hospitalizations but may reduce atherosclerotic events, and their use may be considered in an individualized manner; and (3) in patients with HF and reduced ejection fraction, the use of GLP-1 RAs warrants caution due to potential risk of worsening HF events and arrhythmias, pending risk-benefit data from further studies.

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The rise in the use of social media networks has increased the prevalence of cyberbullying, and time is paramount to reduce the negative effects that derive from those behaviours on any social media platform. This paper aims to study the early detection problem from a general perspective by carrying out experiments over two independent datasets (Instagram and Vine), exclusively using users' comments. We used textual information from comments over baseline early detection models (fixed, threshold, and dual models) to apply three different methods of improving early detection. First, we evaluated the performance of Doc2Vec features. Finally, we also presented multiple instance learning (MIL) on early detection models and we assessed its performance. We applied timeawareprecision (TaP) as an early detection metric to asses the performance of the presented methods. We conclude that the inclusion of Doc2Vec features improves the performance of baseline early detection models by up to 79.6%. Moreover, multiple instance learning shows an important positive effect for the Vine dataset, where smaller post sizes and less use of the English language are present, with a further improvement of up to 13%, but no significant enhancement is shown for the Instagram dataset.

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BACKGROUND: Thyroid dysfunction is common in patients with heart failure (HF). Impaired conversion of free T4 (FT4) into free T3 (FT3) is thought to occur in these patients, decreasing the availability of FT3 and contributing to HF progression. In HF with preserved ejection fraction (HFpEF), it is not known whether changes in conversion of thyroid hormones (THs) are associated with clinical status and outcomes. OBJECTIVES: The objective of this study was to evaluate the association of FT3/FT4 ratio and TH with clinical, analytical, and echocardiographic parameters, as well as their prognostic impact in individuals with stable HFpEF. METHODS: We evaluated 74 HFpEF participants of the NETDiamond cohort without known thyroid disease. We performed regression modeling to study the associations of TH and FT3/FT4 ratio with clinical, anthropometric, analytical, and echocardiographic parameters, and survival analysis to evaluate associations with the composite of diuretic intensification, urgent HF visit, HF hospitalization, or cardiovascular death over a median follow-up of 2.8 years. RESULTS: The mean age was 73.7 years and 62% were men. The mean FT3/FT4 ratio was 2.63 (standard deviation: 0.43). Subjects with lower FT3/FT4 ratio were more likely to be obese and have atrial fibrillation. Lower FT3/FT4 ratio was associated with higher body fat (ß = -5.60 kg per FT3/FT4 unit, p = 0.034), higher pulmonary arterial systolic pressure (PASP) (ß = -10.26 mm Hg per FT3/FT4 unit, p = 0.002), and lower left ventricular ejection fraction (LVEF) (ß = 3.60% per FT3/FT4 unit, p = 0.008). Lower FT3/FT4 ratio was associated with higher risk for the composite HF outcome (HR = 2.50, 95% CI: 1.04-5.88, per 1-unit decrease in FT3/FT4, p = 0.041). CONCLUSIONS: In patients with HFpEF, lower FT3/FT4 ratio was associated with higher body fat, higher PASP, and lower LVEF. Lower FT3/FT4 predicted a higher risk of diuretic intensification, urgent HF visits, HF hospitalization, or cardiovascular death. These findings suggest that decreased FT4 to FT3 conversion might be a mechanism associated with HFpEF progression.

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