Abstract Purpose The landiolol and organ failure in patients with septic shock (STRESS-L study) included a pre-planned sub-study to assess the effect of landiolol treatment on inflammatory and metabolomic markers. Methods Samples collected from 91 patients randomised to STRESS-L were profiled for immune and metabolomic markers. A panel of pro- and anti-inflammatory cytokines were measured through commercially acquired multiplex Luminex assays and statistically analysed by individual and cluster-level analysis (patient). Metabolite fingerprinting was carried out by flow infusion electrospray ionisation high-resolution mass spectrometry and metabolomic data were analysed using the R-based platform MetaboAnalyst. The metabolites were identified using DIMEdb (dimedb.ibers.aber.ac.uk) from their mass/charge ratios. These metabolomic data were also re-analysed using individual and cluster-level analysis. The individual-level models were adjusted for confounders, such as age, sex, noradrenaline dosage and patient (random effect). Results Analysis was undertaken at cluster- and individual-level. There were no significant differences in cytokine concentration level between trial arms nor survivors and non-survivors over the duration of the observations from day 1 to day 4. Metabolomic analysis showed some separation in the levels of ceramides and cardiolipins between those who survived and those who died. Following adjusted analysis for confounders, plasma metabolite concentrations remained statistically different between landiolol and standard care arms for succinic acid, l -tryptophan, l -alanine, 2,2,2-trichloroethanol, lactic acid and d -glucose. Conclusions In a study of ICU patients with established septic shock and a tachycardia, landiolol treatment used to reduce the heart rate from above 95 to a range between 80 and 94 beats per minute did not induce significant cytokine changes. d -Glucose, lactic acid, succinic acid, l -alanine, l -tryptophan and trichloroethanol were pathways that may merit further investigation. Trial Registration : EU Clinical Trials Register Eudra CT: 2017-001785-14 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-001785-14/GB ); ISRCTN registry Identifier: ISRCTN12600919 ( https://www.isrctn.com/ISRCTN12600919 ).
Postoperative morbidity and mortality in patients undergoing major emergency gastrointestinal surgery are a major burden on healthcare systems. Optimal management of perioperative intravenous fluids may reduce mortality rates and improve outcomes from surgery. Previous small trials of cardiac-output guided haemodynamic therapy algorithms in patients undergoing gastrointestinal surgery have suggested this intervention results in reduced complications and a modest reduction in mortality. However, this existing evidence is based mainly on elective (planned) surgery, with little evaluation in the emergency setting. There are fundamental clinical and pathophysiological differences between the planned and emergency surgical setting which may influence the effects of this intervention. A large definitive trial in emergency surgery is needed to confirm or refute the potential benefits observed in elective surgery and to inform widespread clinical practice.
Importance Patients with septic shock undergo adrenergic stress, which affects cardiac, immune, inflammatory, and metabolic pathways. β-Blockade may attenuate the adverse effects of catecholamine exposure and has been associated with reduced mortality. Objectives To assess the efficacy and safety of landiolol in patients with tachycardia and established septic shock requiring prolonged (>24 hours) vasopressor support. Design, Setting, and Participants An open-label, multicenter, randomized trial involving 126 adults (≥18 years) with tachycardia (heart rate ≥95/min) and established septic shock treated for at least 24 hours with continuous norepinephrine (≥0.1 μg/kg/min) in 40 UK National Health Service intensive care units. The trial ran from April 2018 to December 2021, with early termination in December 2021 due to a signal of possible harm. Intervention Sixty-three patients were randomized to receive standard care and 63 to receive landiolol infusion. Main Outcomes and Measures The primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score from randomization through 14 days. Secondary outcomes included mortality at days 28 and 90 and the number of adverse events in each group. Results The trial was stopped prematurely on the advice of the independent data monitoring committee because it was unlikely to demonstrate benefit and because of possible harm. Of a planned 340 participants, 126 (37%) were enrolled (mean age, 55.6 years [95% CI, 52.7 to 58.5 years]; 58.7% male). The mean (SD) SOFA score in the landiolol group was 8.8 (3.9) compared with 8.1 (3.2) in the standard care group (mean difference [MD], 0.75 [95% CI, −0.49 to 2.0]; P = .24). Mortality at day 28 after randomization in the landiolol group was 37.1% (23 of 62) and 25.4% (16 of 63) in the standard care group (absolute difference, 11.7% [95% CI, −4.4% to 27.8%]; P = .16). Mortality at day 90 after randomization was 43.5% (27 of 62) in the landiolol group and 28.6% (18 of 63) in the standard care group (absolute difference, 15% [95% CI, −1.7% to 31.6%]; P = .08). There were no differences in the number of patients having at least one adverse event. Conclusion and Relevance Among patients with septic shock with tachycardia and treated with norepinephrine for more than 24 hours, an infusion of landiolol did not reduce organ failure measured by the SOFA score over 14 days from randomization. These results do not support the use of landiolol for managing tachycardia among patients treated with norepinephrine for established septic shock. Trial Registration EU Clinical Trials Register Eudra CT: 2017-001785-14 ; isrctn.org Identifier: ISRCTN12600919
Abstract Aims The aim is to describe the rationale, design, delivery, and baseline characteristics of the Stroke prevention and rhythm control Treatment: Evaluation of an Educational programme of the European society of cardiology in a cluster-Randomized trial in patients with Atrial Fibrillation (STEEER-AF) trial. Methods and results STEEER-AF is a pragmatic trial designed to objectively and robustly determine whether guidelines are adhered to in routine practice and evaluate a targeted educational programme for healthcare professionals. Seventy centres were randomized in six countries (France, Germany, Italy, Poland, Spain, and UK; 2022–23). The STEEER-AF centres recruited 1732 patients with a diagnosis of atrial fibrillation (AF), with a mean age of 68.9 years (SD 11.7), CHA2DS2-VASc score of 3.2 (SD 1.8), and 647 (37%) women. Eight hundred and forty-three patients (49%) were in AF at enrolment and 760 (44%) in sinus rhythm. Oral anticoagulant therapy was prescribed in 1543 patients (89%), with the majority receiving direct oral anticoagulants (1378; 89%). Previous cardioversion, antiarrhythmic drug therapy, or ablation was recorded in 836 patients (48.3%). Five hundred fifty-one patients (31.8%) were currently receiving an antiarrhythmic drug, and 446 (25.8%) were scheduled to receive a future cardioversion or ablation. The educational programme engaged 195 healthcare professionals across centres randomized to the intervention group, consisting of bespoke interactive online learning and reinforcement activities, supported by national expert trainers. Conclusion The STEEER-AF trial was successfully deployed across six European countries to investigate guideline adherence in real-world practice and evaluate if a structured educational programme for healthcare professionals can improve patient-level care. Clinical Trial Registration Clinicaltrials.gov, NCT04396418.
Artificial intelligence (AI) is increasingly being utilized in healthcare. This article provides clinicians and researchers with a step-wise foundation for high-value AI that can be applied to a variety of different data modalities. The aim is to improve the transparency and application of AI methods, with the potential to benefit patients in routine cardiovascular care. Following a clear research hypothesis, an AI-based workflow begins with data selection and pre-processing prior to analysis, with the type of data (structured, semi-structured, or unstructured) determining what type of pre-processing steps and machine-learning algorithms are required. Algorithmic and data validation should be performed to ensure the robustness of the chosen methodology, followed by an objective evaluation of performance. Seven case studies are provided to highlight the wide variety of data modalities and clinical questions that can benefit from modern AI techniques, with a focus on applying them to cardiovascular disease management. Despite the growing use of AI, further education for healthcare workers, researchers, and the public are needed to aid understanding of how AI works and to close the existing gap in knowledge. In addition, issues regarding data access, sharing, and security must be addressed to ensure full engagement by patients and the public. The application of AI within healthcare provides an opportunity for clinicians to deliver a more personalized approach to medical care by accounting for confounders, interactions, and the rising prevalence of multi-morbidity.
Background Burn injuries are the fourth most common type of trauma and are associated with substantial morbidity and mortality. The impact of burn injury is clinically significant as burn injuries often give rise to exuberant scarring. Hypertrophic scarring (HTS) is a particular concern as up to 70% of burns patients develop HTS. Laser therapy is used for treating HTS and has shown positive clinical outcomes, although the mechanisms remain unclear limiting approaches to improve its effectiveness. Emerging evidence has shown that fibroblasts and senescent cells are important modifiers of scarring. This study aims to investigate the cellular kinetics in HTS after laser therapy, with a focus on the association of scar reduction with the presence of senescent cells. Methods We will conduct a multicentre, intra-patient, single-blinded, randomised controlled longitudinal pilot study with parallel assignments to achieve this objective. 60 participants will be recruited to receive 3 interventional ablative fractional CO 2 laser treatments over a 12-month period. Each participant will have two scars randomly allocated to receive either laser treatment or standard care. Biopsies will be obtained from laser-treated, scarred-no treatment and non-scarred tissues for immune-histological staining to investigate the longitudinal kinetics of p16 INK4A+ -senescent cells and fibroblast subpopulations (CD90 + /Thy1 + and αSMA + ). Combined subjective scar assessments including Modified Vancouver Scar Scale, Patient and Observer Scar Assessment Scale and Brisbane Burn Scar Impact Profile; and objective assessment tools including 3D-Vectra-H1 photography, DermaScan ® Cortex, Cutometer ® and ColoriMeter ® DSMIII will be used to evaluate clinical outcomes. These will then be used to investigate the association between senescent cells and scar reduction after laser therapy. This study will also collect blood samples to explore the systemic biomarkers associated with the response to laser therapy. Discussion This study will provide an improved understanding of mechanisms potentially mediating scar reduction with laser treatment, which will enable better designs of laser treatment regimens for those living with HTS. Trial registration ClinicalTrials.gov: NCT04736251 .
One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood
Abstract Background Burn injuries are the fourth most common type of trauma and are associated with substantial morbidity and mortality. The impact of burn injury is clinically significant as burn injuries often give rise to exuberant scarring. Hypertrophic scarring (HTS) is a particular concern as up to 70% of burns patients develop HTS. Laser therapy is used for treating HTS and has shown positive clinical outcomes, although the mechanisms remain unclear limiting approaches to improve its effectiveness. Emerging evidence has shown that fibroblasts and senescent cells are important modifiers of scarring. This study aims to investigate the cellular kinetics in HTS after laser therapy, with a focus on the association of scar reduction with the presence of senescent cells. Methods We will conduct a multicentre, intra-patient, single-blinded, randomised controlled longitudinal pilot study with parallel assignments to achieve this objective. 60 participants will be recruited to receive 3 interventional ablative fractional CO 2 laser treatments over a 12-month period. Each participant will have two scars randomly allocated to receive either laser treatment or standard care. Biopsies will be obtained from laser-treated, scarred- no treatment and non-scarred tissues for immune-histological staining to investigate the longitudinal kinetics of p16 INK4A+ -senescent cells and fibroblast subpopulations (CD90 + /Thy1 + and αSMA + ). Combined subjective scar assessments including Modified Vancouver Scar Scale, Patient and Observer Scar Assessment Scale and Brisbane Burn Scar Impact Profile; and objective assessment tools including 3D-Vectra-H1 photography, DermaScan ® Cortex, Cutometer ® and ColoriMeter ® DSMIII will be used to evaluate clinical outcomes. These will then be used to investigate the association between senescent cells and scar reduction after laser therapy. This study will also collect blood samples to explore the systemic biomarkers associated with the response to laser therapy. Discussion This study will provide an improved understanding of mechanisms potentially mediating scar reduction with laser treatment, which will enable better designs of laser treatment regimens for those living with HTS. Trial registration ClinicalTrials.gov: NCT04736251 .
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