Conflicts of interest in clinical practice: lessons learned from cardiovascular medicine.

Cardiovascular diseases represent a major burden worldwide, and clinical trials are critical to define treatment improvements. Since various conflicts of interest (COIs) may influence trials at multiple levels, cardiovascular research represents a paradigmatic example to analyze their effects and manage them effectively to re-establish the centrality of evidence-based medicine.Despite the manifest role of industry, COIs may differently affect both sponsored and non-sponsored studies in many ways. COIs influence may start from the research question, data collection and adjudication, up to result reporting, including the spin phenomenon. Outcomes and endpoints (especially composite) choice and definitions also represent potential sources for COIs interference. Since large randomized controlled trials significantly influence international guidelines, thus impacting also clinical practice, their critical assessment for COIs is mandatory. Despite specific protocols aimed to mitigate COI influence, even scientific societies and guideline panels may not be totally free from COIs, negatively affecting their accountability and trustworthiness.Shared rules, awareness of COI mechanisms and transparency with external data access may help promoting evidence-based research and mitigate COIs impact. Managing COIs effectively should preserve public trust in the cardiovascular profession without compromising the positive relationships between investigators and industry.

ENPP1 induces blood-brain barrier dysfunction and promotes brain metastasis formation in HER2-positive breast cancer.

BACKGROUND: Brain metastasis (BrM) is a devastating end-stage neurological complication that occurs in up to 50% of HER2+ breast cancer patients. Understanding how disseminating tumor cells manage to cross the blood-brain barrier (BBB) is essential for developing effective preventive strategies. We identified the ecto-nucleotidase ENPP1 as specifically enriched in the secretome of HER2+ brain metastatic cells, prompting us to explore its impact on BBB dysfunction and BrM formation. METHODS: We used in vitro BBB and in vivo premetastatic mouse models to evaluate the effect of tumor-secreted ENPP1 on brain vascular permeability. BBB integrity was analyzed by real-time fluorescence imaging of 20 kDa Cy7.5-dextran extravasation and immunofluorescence staining of adherens and tight junction proteins. Pro-metastatic effects of ENPP1 were evaluated in an experimental brain metastatic model. RESULTS: Systemically secreted ENPP1 from primary breast tumors impaired the integrity of BBB with loss of tight and adherens junction proteins early before the onset of BrM. Mechanistically, ENPP1 induced endothelial cell dysfunction by impairing insulin signaling and its downstream AKT/GSK3ß/ß-catenin pathway. Genetic ablation of ENPP1 from HER2+ brain metastatic cells prevented endothelial cell dysfunction and reduced metastatic burden while prolonging the overall and metastasis-free survival of mice. Furthermore, plasmatic ENPP1 levels correlate with brain metastatic burden and inversely with overall survival. CONCLUSIONS: We demonstrated that metastatic breast cancer cells exploit the ENPP1 signaling for cell transmigration across the BBB and brain colonization. Our data implicate ENPP1 as a potential biomarker for poor prognosis and early detection of BrM in HER2+ breast cancer.

A Review of Artificial Intelligence and Machine Learning in Product Life Cycle Management.

The pursuit of harnessing data for knowledge creation has been an enduring quest, with the advent of machine learning and artificial intelligence (AI) marking significant milestones in this journey. Machine Learning (ML), a subset of AI, emerged as the practice of employing mathematical models to enable computers to learn and improve autonomously based on their experiences. In the pharmaceutical and biopharmaceutical sectors, a significant portion of manufacturing data remains untapped or insufficient for practical use. Recognizing the potential advantages of leveraging available data for process design and optimization, manufacturers face the daunting challenge of data utilization. Diverse proprietary data formats and parallel data generation systems compound the complexity. The transition to Pharma 4.0 necessitates a paradigm shift in data capture for manufacturing and process operations. This paper highlights the pivotal role of artificial intelligence in converting process data into actionable knowledge to support critical functions throughout the whole process life cycle. Furthermore, it underscores the importance of maintaining compliance with data integrity guidelines, as mandated by regulatory bodies globally. Embracing AI-driven transformations is a crucial step toward shaping the future of the pharmaceutical industry, ensuring its competitiveness and resilience in an evolving landscape.

The Challenge of Managing a Primary Aortic Mural Thrombus: Outcomes and Technical Considerations.

Background: Embolization to multiple arterial beds associated with primary aortic mural thrombus (PAMT) could result in high morbidity and mortality. There are no recommendations to dictate the best management. This study aims to describe our experience in managing this rare disease. Methods: A retrospective review of all patients affected by PAMT treated at our institution between January 2015 and December 2021 was performed. Recorded data included demographics, prothrombotic risk factors, imaging findings, clinical presentation, and treatment. Primary outcomes comprised thrombus recurrence, major amputation, and death. Results: Thirteen patients with PAMT have been included. The median age was 52 years (36-68 years), and the male/female ratio was 1:1.6. The diagnosis of PAMT was made by computed tomography angiography (CTA) in all cases. Prothrombotic conditions were identified in 92% of cases, and most patients (92%) had thoracic PAMT. The most common presentation was acute limb ischemia after thrombus embolization (85%), requiring surgical revascularization. Anticoagulation was promptly started in all patients. Two patients developed heparin-induced thrombocytopenia. Recurrence of embolization/thrombosis was observed in 54% of patients; two underwent endovascular thrombus exclusion with a stent graft. We identified one PAMT-related death and one major amputation with a median follow-up time of 39 months (12-64 months). Conclusion: Anticoagulation alone as initial therapy could completely resolve PAMT but is associated with high embolization recurrence. Thoracic endovascular aortic repair is feasible and could prevent additional embolization. However, the criteria for its use as a first-line therapy still need to be defined. Our study highlights the importance of closely monitoring these patients.

Renal screening sonography-A comparative study in a Portuguese basic emergency service.

INTRODUCTION: Renal Point-of-Care Ultrasound (POCUS) is a screening modality that aids in clinical decision-making for patients with suspected renal colic. This study intends to compare the accuracy and pertinence of sonographic findings obtained by a sonographer in a Basic Emergency Service (BES) with the imaging findings at the Referral Hospital (RH). METHODS: Thirty-one patients suspected of having renal pathology underwent initial sonography screening with POCUS at the BES and were subsequently referred to the RH for additional imaging examinations. The results of both examinations were compared to verify whether the findings from the BES were confirmed by the radiologist in the RH and to ensure that the patient referrals from BES to RH were appropriate. RESULTS: In our sample, the majority of patients (80%) exhibited varying degrees of pyelocaliceal distension, with nearly half (48%) patients presenting obstructions. A strong association between the sonographic findings in the BES and the RH was found in the variables 'Dilatation of pyelocaliceal system' (V = 0.895; P = 0.00), 'Simple cystic formation' (V = 0.878; P = 0.000), respectively. There was a statistically significant correlation between BES and RH findings, indicating a strong association between these two variables, respectively (k = 0.890; P = 0.000) and (k = 0.870; P = 0.000). There was also a strong statistically significant correlation in the ultrasonographic findings between BES and RH performers (k = 0.890; P = 0.000 and k = 0.870; P = 0.000). In this research, an achieved sensitivity of 96% and a specificity of 85% were demonstrated in the identification of pyelocaliceal dilatation. CONCLUSION: Renal POCUS screening successfully detected abnormalities in the urinary system of patients suspected of having renal colic. The sonographic findings at the BES had a good correlation with the complementary imaging results obtained at the RH in Portugal. These results suggest that Radiographers/Sonographers can have an important role in the preliminary assessment of urgent renal pathology in remote areas, contributing to a correct referral and early treatment.

Beyond Restrictive: Sleeve Gastrectomy to Single Anastomosis Duodeno-Ileal Bypass with Sleeve Gastrectomy as a Spectrum of One Single Procedure.

INTRODUCTION: Single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) is a restrictive/hypoabsorptive procedure recommended for patients with obesity class 3. For safety reasons, SADI-S can be split into a two-step procedure by performing a sleeve gastrectomy (SG) first. This stepwise approach also provides an unprecedented opportunity to disentangle the weight loss mechanisms triggered by each component. The objective was to compare weight trajectories and post-prandial endocrine and metabolic responses of patients with obesity class 3 submitted to SADI-S or SG as the first step of SADI-S. METHODS: Subjects submitted to SADI-S (n = 7) or SG (n = 7) at a tertiary referral public academic hospital underwent anthropometric evaluation and a liquid mixed meal tolerance test (MMTT) pre-operatively and at 3, 6, and 12 months post-operatively. RESULTS: Anthropometric parameters, as well as metabolic and micronutrient profiles, were not significantly different between groups, neither before nor after surgery. There were no significant differences in fasting or post-prandial glucose, insulin, C-peptide, ghrelin, insulin secretion rate, and insulin clearance during the MMTT between subjects submitted to SADI-S and SG. There was no lost to follow-up. CONCLUSIONS: The restrictive component seems to be the main driver for weight loss and metabolic adaptations observed during the first 12 months after SADI-S, given that the weight trajectories and metabolic profiles do not differ from SG. These data provide support for surgeons' choice of a two-step SADI-S without jeopardizing the weight loss outcomes.

Cutaneous Mucormycosis in a Young Immunocompetent Trauma Patient: A Case Report.

Introduction: Mucormycosis, a rare and life-threatening infection, is caused by microorganisms of the Mucorales order. It affects almost exclusively immunocompromised and diabetic patients, requiring extensive surgical debridement and prolonged antifungal therapy. Discussion/Results: We report the case of a 26-year-old immunocompetent woman, presenting with cutaneous mucormycosis after suffering blunt force trauma. This rare occurrence of mucormycosis in an immunocompetent patient reinforces the importance of elevated clinical suspicion and early initiation of adequate surgical and antifungal treatment. Conclusion: Mucormycosis is a challenging condition with potentially devastating consequences. Timely diagnosis and appropriate management are vital to mitigate the morbidity and mortality associated with this condition. LEARNING POINTS: Cutaneous mucormycosis is a rare life-threatening infection that affects mainly immunocompromised patients.Certain circumstances warrant a high index of clinical suspicion in immunocompetent patients, and indicate histopathological examination.Treatment involves a multidisciplinary approach with aggressive surgical debridement, antifungal therapy, and elimination of risk factors.

Unveiling the role of osteosarcoma-derived secretome in premetastatic lung remodelling.

BACKGROUND: Lung metastasis is the most adverse clinical factor and remains the leading cause of osteosarcoma-related death. Deciphering the mechanisms driving metastatic spread is crucial for finding open therapeutic windows for successful organ-specific interventions that may halt or prevent lung metastasis. METHODS: We employed a mouse premetastatic lung-based multi-omics integrative approach combined with clinical features to uncover the specific changes that precede lung metastasis formation and identify novel molecular targets and biomarker of clinical utility that enable the design of novel therapeutic strategies. RESULTS: We found that osteosarcoma-bearing mice or those preconditioned with the osteosarcoma cell secretome harbour profound lung structural alterations with airway damage, inflammation, neutrophil infiltration, and extracellular matrix remodelling with increased deposition of fibronectin and collagens by resident stromal activated fibroblasts, favouring the adhesion of disseminated tumour cells. Systemic-induced microenvironmental changes, supported by transcriptomic and histological data, promoted and accelerated lung metastasis formation. Comparative proteome profiling of the cell secretome and mouse plasma identified a large number of proteins involved in extracellular-matrix organization, cell-matrix adhesion, neutrophil degranulation, and cytokine-mediated signalling, consistent with the observed lung microenvironmental changes. Moreover, we identified EFEMP1, an extracellular matrix glycoprotein exclusively secreted by metastatic cells, in the plasma of mice bearing a primary tumour and in biopsy specimens from osteosarcoma patients with poorer overall survival. Depletion of EFEMP1 from the secretome prevents the formation of lung metastasis. CONCLUSIONS: Integration of our data uncovers neutrophil infiltration and the functional contribution of stromal-activated fibroblasts in ECM remodelling for tumour cell attachment as early pro-metastatic events, which may hold therapeutic potential in preventing or slowing the metastatic spread. Moreover, we identified EFEMP1, a secreted glycoprotein, as a metastatic driver and a potential candidate prognostic biomarker for lung metastasis in osteosarcoma patients. Osteosarcoma-derived secreted factors systemically reprogrammed the lung microenvironment and fostered a growth-permissive niche for incoming disseminated cells to survive and outgrow into overt metastasis. Daily administration of osteosarcoma cell secretome mimics the systemic release of tumour-secreted factors of a growing tumour in mice during PMN formation; Transcriptomic and histological analysis of premetastatic lungs revealed inflammatory-induced stromal fibroblast activation, neutrophil infiltration, and ECM remodelling as early onset pro-metastatic events; Proteome profiling identified EFEMP1, an extracellular secreted glycoprotein, as a potential predictive biomarker for lung metastasis and poor prognosis in osteosarcoma patients. Osteosarcoma patients with EFEMP1 expressing biopsies have a poorer overall survival.

Discrepancies between Screening Sonography and Ultrasound in Emergency Department - A Case Report.

INTRODUCTION: This case report presents a discrepancy in sonographic findings between a screening sonography performed by a Sonographer in the Basic Emergency Service (BES) and a subsequent ultrasound performed by a Radiologist physician in a Referral Hospital (RH). The aim of this report is to discuss the possible reasons for the discrepancy and its implications for patient care. CASE PRESENTATION: A patient with a history of epigastric pain and vomiting underwent screening sonography in a BES, which suggested Intrahepatic Biliary Dilatation Duct (IHBD) and main pancreatic duct dilatation. The patient was subsequently referred to the RH for further evaluation. However, the Radiologist in the RH did not confirm any of the initial suspicions from BES through a normal ultrasound procedure. The discrepancy raises questions regarding the quality of the screening ultrasound, misinterpretation of the BES images, or the potential for ambiguity in the point of care ultrasound (POCUS) exam. CONCLUSION: The differences in sonographic findings between BES and RH, in this case, suggest that the improvement of the patient's clinical condition and therapeutic interventions may have contributed to the discrepancy. Further investigation and standardization of POCUS training and interpretation may improve diagnostic accuracy and patient outcomes.

Diffuse Peritonitis Caused by Splenic Abscess After Laparoscopic Sleeve Gastrectomy: A Case Report.

A splenic abscess (SA) following sleeve gastrectomy (SG) is a rare manifestation of a gastric leak (GL). The clinical findings include fever, abdominal pain, leukocytosis, and an elevated C-reactive protein. A computed tomography scan is diagnostic and can show signs of GL, or diffuse peritonitis. Treatment can either be non-operative (including large-spectrum antibiotics and percutaneous drainage) or surgical (including splenectomy). We present the case of a 41-year-old female patient with SA, with septic shock and diffuse peritonitis, successfully treated with a splenectomy three months post-SG.

The ISCHEMIA trial revisited: setting the record straight on the benefits of coronary bypass surgery and the misinterpretation of a landmark trial.

OBJECTIVES: The ISCHEMIA trial is a landmark study that has been the subject of heated debate within the cardiovascular community. In this analysis of the ISCHEMIA trial, we aim to set the record straight on the benefits of coronary artery bypass grafting (CABG) and the misinterpretation of this landmark trial. We sought to clarify and reorient this misinterpretation. METHODS: We herein analyse the ISCHEMIA trial in detail and describe how its misinterpretation has led to an erroneous guideline recommendation downgrading for prognosis-altering surgical therapy in these at-risk patients. RESULTS: The interim ISCHEMIA trial findings align with previous evidence where CABG reduces the long-term risks of myocardial infarction and mortality in advanced coronary artery disease. The trial outcomes of a significantly lower rate of cardiovascular mortality and a higher rate of non-cardiovascular mortality with the invasive strategy are explained according to landmark evidence. CONCLUSIONS: The ISCHEMIA trial findings are aligned with previous evidence and should not be used to downgrade recommendations in recent guidelines for the indisputable benefits of CABG.

Institutional Experience With Venous Aneurysms - Insights On The Natural History And Outcomes Of Surgical Treatment.

INTRODUCTION: Venous aneurysms are rare, so their natural history is not fully understood. Indications for treatment are often determined by the location and size of the aneurysm; however, considering the scarcity of data, there are no specific recommendations. Surgery is the mainstay for venous aneurysm treatment, but some authors reported successful endovascular treatment. We intend to describe our experience with this type of rare disorder. METHODS: A post hoc observational study of a prospectively maintained registry including consecutive patients admitted with the diagnosis of a venous aneurysm at different locations between January 2007 and September 2021. Demographic data, anatomic location, and medical history, including trauma or venous surgery, were analyzed. All vascular reconstructions and outcomes have been evaluated. RESULTS: We identified 30 venous aneurysms in 24 patients. Fifteen patients were male (63%). The most common anatomical location was the popliteal vein (n=19; 63%). Four patients had multiple venous aneurysms, and three patients had synchronous arterial aneurysms. Twelve (63%) of the popliteal vein aneurysms identified were surgically treated, most commonly by tangential aneurysmectomy and lateral venorrhaphy. The average diameter at the time of surgery was 22,8±3,6 mm. After discharge, all patients were anticoagulated for 6 to 12 months, in most cases with rivaroxaban. With a median follow-up time of 32 months (12 - 168 months), primary patency was 92%. Aneurysm recurrence was only observed in one case (1/12; 8%) with non-occlusive thrombosis of the aneurysm 14 years after surgery. One patient had a 21 mm gemelar vein aneurysm, having been proposed for surgery, with thrombosis before the intervention. Two patients had common femoral vein aneurysms treated with partial aneurysmectomy and lateral venorrhaphy without thromboembolic events during follow-up. Two patients presented with portal system aneurysms, one associated with portal hypertension. No treatment was performed, and an increase in aneurysm size was observed during follow-up. Another patient presented with acute deep vein thrombosis on chronically thrombosed bilateral iliac vein aneurysms. Three patients had aneurysms of the superficial venous system associated with previous trauma, which were treated with simple ligation and excision. CONCLUSION: Venous aneurysms are rare and most commonly located in the popliteal vein, which seems to be associated with chronic venous disease. Treating these aneurysms, even without symptoms, can be important to avoid thromboembolic complications. However, close long-term follow-up with duplex ultrasound should be considered to detect late recurrence. Aneurysms from other locations are even rarer, and treatment decisions should be individualized, weighing the risks and benefits of the intervention.