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Immune checkpoint inhibitor (ICI) therapy is a rapidly expanding pillar of cancer treatment, but it carries the risk of immune-related adverse events. Among the most fatal is ICI-related myocarditis (ICIRM). Cardiac magnetic resonance (CMR) imaging is the non-invasive current gold standard for diagnosis, with significant disparities regarding availability and utilisation. The vast majority of ICIRM cases are reported in high-income countries (HICs), reflecting not only patterns of ICI use, but also a profound diagnostic gap in low- and middle-income countries (LMICs). LMICs face barriers to CMR access, including a stark deficit of MRI scanners, with approximately 1 scanner per million people in LMICs versus 26 per million people in HICs, prohibitive costs, and a critical shortage of trained radiologists and cardiologists. The inequity means that as ICI therapy becomes increasingly accessible worldwide, patients in resource-limited settings will be at a high-risk of undiagnosed and untreated ICIRM. Our paper issues a call to address this critical healthcare disparity. To improve CMR access for ICIRM diagnosis in LMICs, a multi-pronged strategy is imperative – Governmental support and policy change to prioritise infrastructure investment and integrate CMR into national health strategies; targeted educational programmes, such as the SWiM and ‘train the trainer’ initiatives, to build local expertise in CMR acquisition and interpretation; adoption of technological innovations, including cost-effective rapid CMR protocols and artificial intelligence (AI) tools that can reduce scan times.

Background: Cardiovascular comorbidities such as hypertension and inflammatory response dysregulation are associated with worse COVID-19 prognoses. Different cytokines have been proposed to play vital pathophysiological roles in COVID-19 progression, but appropriate prognostic biomarkers remain lacking. We hypothesized that the combination of immunological and clinical variables at admission could predict the clinical progression of COVID-19 in hypertensive patients. Methods: The levels of biomarkers, including C-reactive protein, lymphocytes, monocytes, and a panel of 29 cytokines, were measured in blood samples from 167 hypertensive patients included in the BRACE-CORONA trial. The primary outcome was the highest score during hospitalization on the modified WHO Ordinal Scale for Clinical Improvement. The probability of progression to severe disease was estimated using a logistic regression model that included clinical variables and biomarkers associated significantly with the primary outcome. Results: During hospitalization, 13 (7.8%) patients showed progression to more severe forms of COVID-19, including three deaths. Obesity, diabetes, oxygen saturation, lung involvement on computed tomography examination, the C-reactive protein level, levels of 15 cytokines, and lymphopenia on admission were associated with progression to severe COVID-19. Elevated levels of interleukin-10 and interleukin-12 (p70) combined with two or three of the abovementioned clinical comorbidities were associated strongly with progression to severe COVID-19. The risk of progression to severe disease reached 97.5% in the presence of the five variables included in our model. Conclusions: This study demonstrated that interleukin-10 and interleukin-12 (p70) levels, in combination with clinical variables, at hospital admission are key biomarkers associated with an increased risk of disease progression in hypertensive patients with COVID-19.

COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population. We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3–0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed. From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28 899 (34·8%) wins in the therapeutic group and 34 288 (41·3%) in the prophylactic group (win ratio 0·86 [95% CI 0·59–1·22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3·64 [95% CI 1·61–8·27], p=0·0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group. In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation. Coalition COVID-19 Brazil, Bayer SA.

Observational studies have suggested a higher risk of thrombotic events in patients with coronavirus disease 2019 (COVID-19). Moreover, elevated D-dimer levels have been identified as an important prognostic marker in COVID-19 directly associated with disease severity and progression. Prophylactic anticoagulation for hospitalized COVID-19 patients might not be enough to prevent thrombotic events; therefore, therapeutic anticoagulation regimens deserve clinical investigation. ACTION is an academic-led, pragmatic, multicenter, open-label, randomized, phase IV clinical trial that aims to enroll around 600 patients at 40 sites participating in the Coalition COVID-19 Brazil initiative. Eligible patients with a confirmed diagnosis of COVID-19 with symptoms up to 14 days and elevated D-dimer levels will be randomized to a strategy of full-dose anticoagulation for 30 days with rivaroxaban 20 mg once daily (or full-dose heparin if oral administration is not feasible) vs standard of care with any approved venous thromboembolism prophylaxis regimen during hospitalization. A confirmation of COVID-19 was mandatory for study entry, based on specific tests used in clinical practice (RT-PCR, antigen test, IgM test) collected before randomization, regardless of in the outpatient setting or not. Randomization will be stratified by clinical stability at presentation. The primary outcome is a hierarchical analysis of mortality, length of hospital stay, or duration of oxygen therapy at the end of 30 days. Secondary outcomes include the World Health Organization's 8-point ordinal scale at 30 days and the following efficacy outcomes: incidence of venous thromboembolism , acute myocardial infarction, stroke, systemic embolism, major adverse limb events, duration of oxygen therapy, disease progression, and biomarkers. The primary safety outcomes are major or clinically relevant non-major bleeding according to the International Society on Thrombosis and Haemostasis criteria. The ACTION trial will evaluate whether in-hospital therapeutic anticoagulation with rivaroxaban for stable patients, or enoxaparin for unstable patients, followed by rivaroxaban through 30 days compared with standard prophylactic anticoagulation improves clinical outcomes in hospitalized patients with COVID-19 and elevated D-dimer levels.

The Amazon shelf is a key region for intense internal tides (ITs) and nonlinear internal solitary wave (ISWs) generation associated with them. The region shows well-marked seasonal variability (from March to July, MAMJJ, and from August to December, ASOND) of the circulation and stratification, which can both induce changes in the ISW physical characteristics. The description of the seasonal and neap–spring tidal variability in the ISWs off the Amazon shelf is performed for the first time using a meaningful data set composed of 140 MODIS-Terra imagery from 2005 to 2021, where about 500 ISW signatures were identified in the sun glint region. Previous studies have documented the existence of mode-1 ISWs, but the region appears as a newly described hotspot for mode-2 ISWs. ISW packets separated by typical mode-1 (95–170 km; 2.1–3.8 m s−1) and mode-2 (46–85 km; 1.0–1.9 m s−1) IT wavelengths have been identified and mapped coming from different IT generation sites. For each ISW, a group of waves (3 to 10) is generally follows the largest crest. The intra-packet distance between each wave in the group is about 10 to 20 km. Regions of higher occurrence of ISWs are spaced by a IT mode-1 wavelength. We make the assumption that it might correspond to the IT reflection beams at the surface, which may generate newer ISWs. The mean mode-1 and mode-2 inter-packet distances do not show significant differences according to their IT generation sites. The ISW activity is higher (more than 60 % of signatures) during spring tides than neap tides. In the region under the influence of the North Equatorial Counter Current (NECC), ISWs are separated by a mean mode-1 IT wavelength which is 14.3 % higher during ASOND than during MAMJJ due to a deeper thermocline and the reinforcement of the NECC. These ISWs are also characterized by a wider inter-packet distance distribution (higher standard deviation) that may be related to the stronger eddy kinetic energy (EKE) during ASOND compared to MAMJJ. The mean inter-packet distance of mode-2 ISWs remains almost unchanged during the two seasons, but the inter-packet distance distribution is wider in ASOND than in MAMJJ as for mode 1. Note that these results need to be treated with caution, as only few occurrences of mode-2 waves were found during MAMJJ. In the region of the NECC, the direction of propagation for all modes is very similar in MAMJJ (about 30∘ clockwise from the north), whereas, for ASOND, the ISWs propagate in a wider pathway (from 0 to 60∘ clockwise from the north), due to a much larger eddy activity. During ASOND, as the background flux goes further east, the inter-packet distances become larger (4 % for mode 1 and 7.8 % for mode 2). These results show that the reinforcement of the NECC in ASOND appears to play a role in diverting the waves towards the east, increasing their phase velocities and their eastern traveling direction component when compared to MAMJJ. Calculations of the IT velocities using the Taylor–Goldstein equation supported our results regarding the presence of ISWs associated with mode-2 ITs and additionally the IT seasonal variability.

This study investigates the influence of tides on chlorophyll a (CHL) variability in the Brazilian Equatorial Margin using daily GlobColour and MODIS-Aqua CHL data from 2005 to 2021. The impact of the tides is assessed by comparing the spring with the neap tide signals (fortnightly signal, 14.7 d). Results show that, on the shallow Amazon shelf, significant fortnightly CHL variability is likely primarily driven by barotropic tide-induced friction on the shelf that produces significant vertical mixing. On the northwestern shelf, where the Amazon River plume prevails, CHL levels are higher during neap tides, resulting in a negative spring–neap tide CHL difference (GlobColour: −50 %; MODIS-Aqua: −84 %). Conversely, on the northeastern shelf, characterized by low-turbidity waters, CHL levels are higher during spring tides, leading to a positive spring–neap tide CHL difference (GlobColour: +30 %; MODIS-Aqua: +70 %). Offshore, baroclinic tides, also known as internal tides (ITs), seem to enhance the CHL along their pathways with a spatial structure of a wave-like pattern. The positive CHL peaks are spaced by mode-2 wavelengths (about 68 km), with peak values reaching +3.3 % (GlobColour) and +9.0 % (MODIS-Aqua). Analysis shows that the CHL wave-like pattern suggests contributions from mode-1 and mode-2 internal tides, with mode-2 components having higher spectral coherence with the original signal. A 1–3 d lag between higher CHL variability and tidal potential may indicate delayed nutrient mixing post-spring–neap tides. The effects of ITs on CHL are more pronounced than on sea surface temperature.

The ocean region off the Amazon shelf including the shelf break presents a hotspot for internal tide (IT) generation, yet its impact on phytoplankton distribution remains poorly understood. While previous studies have extensively examined the physical characteristics and dynamics of ITs, their biological implications – particularly in nutrient-limited environments – remain underexplored. To address this question, we analyzed a 26 d glider mission deployed over September–October 2021 sampling hydrographic and optical properties (chlorophyll a) at high resolution along an IT pathway as well as satellite chlorophyll a and altimetry data to assess mesoscale interactions. Chlorophyll a dynamics were analyzed under varying IT intensities, comparing strong (HT) and weak (LT) internal tide conditions. Results reveal that ITs drive vertical displacements of the deep chlorophyll maximum (DCM) from 15 to 45 m, accompanied by 50 % expansion in its thickness during HT events. This expansion is observed with a dilution of the chlorophyll a maximum concentration within the DCM depth. While direct turbulence measurements were not collected, the observed vertical redistribution of chlorophyll a is indicative of tidally driven cross-isopycnal exchanges, the only physical mechanism explaining the transfer of biomass above and below the DCM. At the surface, turbulent fluxes provide 38 % of the chlorophyll a input, while the remainder is supplied by in situ biological activity. Notably, total chlorophyll a in the water column increases by 14 %–29 % during high internal tide phases, indicating a net enhancement of primary productivity driven by the combined effects of vertical mixing and stimulated surface-layer biological activity. These findings indicate that internal tides can be an important driver of chlorophyll a distribution and short-term biological variability in our study region. By reshaping the vertical chlorophyll a profile through vertical mixing, active internal tides influence primary productivity and may contribute to carbon cycling, particularly in oligotrophic oceanic environments where both a deep chlorophyll maximum and strong internal tides are present.

The use of rue extract and ginger oleoresin as natural antifouling agents in a silicone matrix was verified in this work. 13 C nuclear magnetic resonance ( 13 C NMR) analysis identified a series of compounds with bactericidal properties in the two investigated natural products. Thermogravimetric analyses showed that the addition of rue extract and ginger oleoresin in the silicone matrix increased the thermal stability of the formed films. Electrochemical impedance spectroscopy analysis showed that the presence of both antifouling agents increases the velocity of water diffusion into the film, improving contact between marine water and the two products. Fourier transform infrared spectroscopy confirms that both antifouling agents were trapped inside the silicone matrix. Bacterial adhesion tests showed that rue extract reduced the adhesion of gram-negative bacteria, Escherichia coli , while ginger oleoresin did not show any significant effect. Optical microscopy images demonstrated that the presence of rue extract slightly increased the film’s porosity without impairing the silicone hydrophobicity, while ginger oleoresin significantly altered the film’s morphology (reducing the water contact angle). Finally, the sample containing rue extract showed excellent results against marine fouling after 6 months of immersion in a real marine environment. The polymer containing ginger oleoresin showed satisfactory results against marine fouling; however, the film showed adhesion failures after 6 months. Graphic abstract

Direct oral anticoagulants (DOACs) for venous thromboembolism (VTE) prevention after major gynecological cancer surgery might be an alternative to parenteral low-molecular-weight heparin (LMWH). Patients undergoing major gynecological cancer surgery were randomized at hospital discharge to receive rivaroxaban 10 mg once daily or enoxaparin 40 mg once daily for 30 days. The primary efficacy outcome was a combination of symptomatic VTE and VTE-related death or asymptomatic VTE at day 30. The primary safety outcome was the incidence of major or clinically relevant nonmajor bleeding. Two hundred and twenty-eight patients were enrolled and randomly assigned to receive rivaroxaban (n = 114)or enoxaparin (n = 114). The trial was stopped due to a lower-than-expected event rate. The primary efficacy outcome occurred in 3.51% of patients assigned to rivaroxaban and in 4.39% of patients assigned to enoxaparin (relative risk 0.80, 95% CI 0.22 to 2.90; p = 0.7344). Patients assigned to rivaroxaban had no primary bleeding event, and 3 patients (2.63%) in the enoxaparin group had a major or CRNM bleeding event (hazard ratio, 0.14; 95% CI, 0.007 to 2.73; P = 0.1963). In patients undergoing major gynecological cancer surgery, thromboprophylaxis with rivaroxaban 10 mg daily for 30 days had similar rates of thrombotic and bleeding events compared to parenteral enoxaparin 40 mg daily. While the power is limited due to not reaching the intended sample size, our results support the hypothesis that DOACs might be an attractive alternative strategy to LMWH to prevent VTE in this high-risk population.

Therapeutic anticoagulation showed inconsistent results in hospitalized patients with COVID-19 and selection of the best patients to use this strategy still a challenge balancing the risk of thrombotic and hemorrhagic outcomes. The present post-hoc analysis of the ACTION trial evaluated the variables independently associated with both bleeding events (major bleeding or clinically relevant non-major bleeding) and the composite outcomes thrombotic events (venous thromboembolism, myocardial infarction, stroke, systemic embolism, or major adverse limb events). Variables were assessed one by one with independent logistic regressions and final models were chosen based on Akaike information criteria. The model for bleeding events showed an area under the curve of 0.63 (95% confidence interval [CI] 0.53 to 0.73), while the model for thrombotic events had an area under the curve of 0.72 (95% CI 0.65 to 0.79). Non-invasive respiratory support was associated with thrombotic but not bleeding events, while invasive ventilation was associated with both outcomes (Odds Ratio of 7.03 [95 CI% 1.95 to 25.18] for thrombotic and 3.14 [95% CI 1.11 to 8.84] for bleeding events). Beyond respiratory support, creatinine level (Odds Ratio [OR] 1.01 95% CI 1.00 to 1.02 for every 1.0 mg/dL) and history of coronary disease (OR 3.67; 95% CI 1.32 to 10.29) were also independently associated to the risk of thrombotic events. Non-invasive respiratory support, history of coronary disease, and creatinine level may help to identify hospitalized COVID-19 patients at higher risk of thrombotic complications.ClinicalTrials.gov: NCT04394377.