Lactate-Induced HBEGF Shedding and EGFR Activation: Paving the Way to a New Anticancer Therapeutic Opportunity.

Cancer cells can release EGF-like peptides, acquiring the capacity of autocrine stimulation via EGFR-mediated signaling. One of these peptides (HBEGF) was found to be released from a membrane-bound precursor protein and is critically implicated in the proliferative potential of cancer cells. We observed that the increased lactate levels characterizing neoplastic tissues can induce the release of uPA, a protease promoting HBEGF shedding. This effect led to EGFR activation and increased ERK1/2 phosphorylation. Since EGFR-mediated signaling potentiates glycolytic metabolism, this phenomenon can induce a self-sustaining deleterious loop, favoring tumor growth. A well characterized HBEGF inhibitor is CRM197, a single-site variant of diphtheria toxin. We observed that, when administered individually, CRM197 did not trigger evident antineoplastic effects. However, its association with a uPA inhibitor caused dampening of EGFR-mediated signaling and apoptosis induction. Overall, our study highlights that the increased glycolytic metabolism and lactate production can foster the activated state of EGFR receptor and suggests that the inhibition of EGFR-mediated signaling can be attempted by means of CRM197 administered with an appropriate protease inhibitor. This attempt could help in overcoming the problem of the acquired resistance to the conventionally used EGFR inhibitors.

Peptides inhibiting the assembly of monomeric human l-lactate dehydrogenase into catalytically active homotetramer decrease the synthesis of lactate in cultured cells.

The energetic metabolism of cancer cells relies on a substantial commitment of pyruvate to the catalytic action of lactate-generating dehydrogenases. This coupling mainly depends on lactate dehydrogenase A (LDH-A), which is overexpressed in different types of cancers, and therefore represents an appealing therapeutic target. Taking into account that the activity of LDHs is exclusively exerted by their tetrameric forms, it was recently shown that peptides perturbing the monomers-to-tetramer assembly inhibit human LDH-A (hLDH-A). However, to identify these peptides, tetrameric hLDH-A was transiently exposed to strongly acidic conditions inducing its dissociation into monomers, which were tested as a target for peptides at low pH. Nevertheless, the availability of native monomeric hLDH-A would allow performing similar screenings under physiological conditions. Here we report on the unprecedented isolation of recombinant monomeric hLDH-A at neutral pH, and on its use to identify peptides inhibiting the assembly of the tetrameric enzyme. Remarkably, the GQNGISDL octapeptide, mimicking the 296-303 portion of hLDH-A C-terminal region, was observed to effectively inhibit the target enzyme. Moreover, by dissecting the action of this octapeptide, the cGQND cyclic tetrapeptide was found to act as the parental compound. Furthermore, we performed assays using MCF7 and BxPC3 cultured cells, exclusively expressing hLDH-A and hLDH-B, respectively. By means of these assays we detected a selective action of linear and cyclic GQND tetrapeptides, inhibiting lactate secretion in MCF7 cells only. Overall, our observations suggest that peptides mimicking the C-terminal region of hLDH-A effectively interfere with protein-protein interactions responsible for the assembly of the tetrameric enzyme.

Ventricular arrhythmias and primary prevention of sudden cardiac death in Anderson-Fabry disease.

The Anderson-Fabry disease (AFD) is a X-linked lysosomal storage disorder due to the deficiency in the α-galactosidase A enzyme. Cardiovascular mortality is a major cause of death in patients with AFD and sudden cardiac death (SCD) is one of the main causes of death. The storage of glycosphingolipid along with ionic channel impairment, inflammation and fibrosis are involved in the arrhythmogenesis. Some risk factors have been associated with ventricular tachycardia (VT)/ventricular fibrillation (VF) and SCD. Left ventricular hypertrophy (LVH), cardiac fibrosis, non-sustained VTs seem to be the most important. Older age and male gender might be associated with higher risk of ventricular arrhythmias and SCD. Currently, the implantable cardioverter-defibrillator (ICD) is recommended in patients with AFD who have survived a cardiac arrest secondary to VT/VF or who experienced sustained VT causing syncope or hemodynamic compromise, and have a life expectancy >1 year. ICD implantation is also recommended in patients considered to be at high risk (e.g., patients with severe LVH or fibrosis). The present review sought to summarize the risk of ventricular arrythmias in AFD, the indications for ICD, focusing on pathophysiology and analyzing the role of possible predictors of arrhythmias in preventing SCD, especially as primary prevention.

Vascular function in patients with advanced heart failure and continuous-flow or pulsatile ventricular assist devices.

BACKGROUND: A significant proportion of patients with heart failure (HF) progress to an advanced stage, which is associated with a substantial increase in morbidity and mortality. These patients may be eligible for advanced treatment strategies such as mechanical circulatory support with ventricular assist devices (VAD). Vascular dysfunction is a hallmark of heart failure pathophysiology and prognosis. However, whether and to what degree the hemodynamic benefits of VADs influence vascular function remain unknown. METHODS AND RESULTS: In this study, we evaluated endothelial vascular function with flow-mediated vasodilatation (FMD) and with flicker-light induced retinal vasodilatation (FID). 34 patients with a VAD (age 58 ± 10 years, 85% male, 74% ischemic heart disease, 26 continuous-flow (CF)-LVAD, and 8 pulsatile biventricular (bi)-VAD) were compared to 34 propensity-matched patients (mean age 62 ± 9 years, 68% male, 59% ischemic heart disease) with advanced HF (AdvHF). Endothelial function of larger arteries (FMD) was significantly better in patients after VAD implantation compared to matched AdvHF patients (7.2 ± 4.6% vs. 5.0 ± 3.2%, p = 0.03), whereas microvascular arteriolar function (FIDart) did not differ (0.99 ± 1.43% vs. 1.1 ± 1.7%, p = 0.78). The arterio-venous ratio (AVR) was higher in the VAD group (0.90 ± 0.06 vs 0.85 ± 0.09, p = 0.01), reflecting wider retinal arteriolar and narrower venular diameters. There was no difference in vascular function between patients with CF-LVAD and pulsatile Bi-VAD. CONCLUSION: In patients with advanced heart failure, VAD implantation was associated with better endothelial function at the level of large arteries, but not in the microcirculation.

A new non-destructive method to decipher the origin of organic matter in fossils using Raman spectroscopy.

Ancient biomolecules provide a unique perspective on the past but are underutilized in paleontology because of challenges in interpreting the chemistry of fossils. Most organically preserved soft tissues in fossils have been altered by thermal maturation during the fossilization process, obscuring original chemistry. Here, we use a comprehensive program of thermal maturation experiments on soft tissues from diverse extant organisms to systematically test whether thermally altered biosignatures can be discriminated using Raman spectroscopy. All experimentally matured samples show chemical signatures that are superficially similar. Comparative analysis of Raman spectra following peak deconvolution, however, reveals strong tissue-specific signals. Application of this approach to fossils from the Bolca (49 Ma) and Libros (10 Ma) Konservat-Lagerstätten successfully discriminates fossil vertebrate soft tissue from that of fossil plants. Critically, our data confirm that a robust interrogation of Raman spectra coupled with multivariate analysis is a powerful tool to shed light on the taxonomic origins of thermally matured fossil soft tissues.

Blood pressure behavior during exercise in patients with diastolic dysfunction and a hypertensive response to exercise.

A hypertensive response to exercise is a precursor leading to hypertension, which is a major risk factor for the development of heart failure and diastolic dysfunction. Herein, we aimed to assess blood pressure (BP) in patients with a hypertensive response to exercise and different degrees of diastolic dysfunction. Between January 2009 and December 2014, 373 patients with a hypertensive response to exercise (HRE) and echocardiographic data assessing diastolic function were enrolled at the University Hospital of Zurich. ANCOVA was used to assess the changes in BP response during exercise testing in individuals with different degrees of diastolic dysfunction. Normalization of systolic BP was blunted in patients with grade II and III diastolic dysfunction after 3 min of recovery in univariable [ß (95%) - 9.2 (-13.8 to - 4.8) p < .001, -16.0 (-23.0 to 9.0) p < .001, respectively] and adjusted models. In fully adjusted models, when taking maximal effort into account, there were no differences with regard to systolic BP during exercise. Patients without diastolic dysfunction achieved higher heart rates (HRs) [both in absolute terms (p < .001) and as a percentage of the calculated maximum (p = .003)] and greater wattage (p < .001) at maximum exertion. The findings of this cross-sectional study suggest that exercise capacity is compromised in patients with diastolic dysfunction. A hypertensive response to exercise and the finding of a blunted BP recovery may help identify patients at risk of developing heart failure.

Sacituzumab govitecan in triple-negative breast cancer: from bench to bedside, and back.

Triple-negative breast cancer (TNBC) represents a major therapeutic challenge due to its heterogeneous and aggressive phenotype, and limited target-specific treatment options. The trophoblast cell surface antigen (Trop-2), a transmembrane glycoprotein overexpressed in various cancers, has emerged as a promising target for TNBC. Sacituzumab govitecan (SG), an antibody-drug conjugate (ADC) that targets Trop-2, has recently entered treatment algorithms for advanced and metastatic TNBC, independently from Trop-2 expression status, with manageable toxicity. Despite the impressive results, questions remain unsolved regarding its efficacy, safety profile, and Trop-2 biological role in cancer. Currently, Trop-2 cannot be designated as a predictive biomarker in SG treatment, albeit its expression correlates with disease outcome, yet its levels are not uniform across all TNBCs. Additionally, data regarding Trop-2 expression variations in primary and metastatic sites, and its interplay with other biomarkers are still ambiguous but mandatory in light of future applications of SG in other indications and settings. This poses the questions of a careful evaluation of the efficacy and toxicity profile of SG in such early stages of disease, and in personalized and combinatorial strategies. Research and clinical data are mandatory to address SG drawbacks and minimize its benefits, to realize its full potential as therapeutic agent in different epithelial tumors.

Bone morphogenic protein-4 availability in the cardiac microenvironment controls inflammation and fibrosis in autoimmune myocarditis.

Myocarditis is an inflammatory heart disease that leads to loss of cardiomyocytes and frequently precipitates fibrotic remodeling of the myocardium, culminating in heart failure. However, the molecular mechanisms underlying immune cell control and maintenance of tissue integrity in the inflamed cardiac microenvironment remain elusive. In this study, we found that bone morphogenic protein-4 (BMP4) gradients maintain cardiac tissue homeostasis by single-cell transcriptomics analyses of inflamed murine and human myocardial tissues. Cardiac BMP pathway dysregulation was reflected by reduced BMP4 serum concentration in patients with myocarditis. Restoration of BMP signaling by antibody-mediated neutralization of the BMP inhibitors gremlin-1 and gremlin-2 ameliorated T cell-induced myocardial inflammation in mice. Moreover, progression to inflammatory cardiomyopathy was blocked through the reduction of fibrotic remodeling and preservation of cardiomyocyte integrity. These results unveil the BMP4-gremlin axis as a druggable pathway for the treatment of myocardial inflammation, limiting the severe sequelae of cardiac fibrosis and heart failure.

Valgus stress knee radiographs accurately anticipate the bone resection in medial unicompartmental knee arthroplasty: Protocol validation using an image-based robotic system.

PURPOSE: The objective of this study was to describe a planning method for medial unicompartmental knee arthroplasty (UKA) implantation using preoperative stress radiographs to measure the thickness of tibial and femoral bone resections and to validate this method with data from an image-based robotic surgery system. Having such method for preoperative planning would be of interest for surgeons performing UKA in order to anticipate optimal bone resection on both tibia and femoral sides. METHODS: A new planning method for medial UKA based on valgus stress knee radiographs validated it with an image-based robotic surgery system (Restoris MCK, MAKO®, Stryker Corporation) was proposed. This retrospective study involved radiographic measurements of 76 patients who underwent image-based robotic medial UKA between April 2022 and February 2023. Preoperative anteroposterior stress radiographs of the knee were used to simulate UKA implantation. The UKA technique was based on Cartier's angle and aimed at restoring the joint line. The total dimension measured was 14 mm (8 mm for minimal tibial component and polyethylene insert + 4 mm for femoral component + 2 mm for safety laxity). Bone resections were measured in the preoperative valgus stress radiographs and then against the intraoperative bone resection data provided by the robotic system. Inter- and intra-observer reliability was assessed using 25 measurements. RESULTS: The mean planned tibial resection measured in the radiographs was 4.3 ± 0.4 [2.9-5.8], while the mean robotic resection was 4.2 ± 0.5 [2.7-5.8] (mean difference = 0.15 mm, 95% confidence interval [CI] [-0.27 to 0.57]). There was a strong correlation between these two values (Pearson's rank R = 0.79, p < 0.001). Intra- and inter-observer reliability were also very strong (Pearson's rank R = 0.91, p < 0.001, and Pearson's rank R = 0.82, p < 0.001, respectively). The mean planned femoral bone resection measured in the radiographs was 2.7 ± 0.7 mm [1-4.5], while the mean robotic resection was 2.5 ± 0.9 [1-5] (mean difference = 0.21 mm, 95% CI [-0.66 to 1.08]). There was a strong correlation between these two values (Pearson's rank R = 0.82, p < 0.001). Intra- and inter-observer reliability were also strong (Pearson's rank R = 0.88, p < 0.001, and Pearson's rank R = 0.84, p < 0.001, respectively). CONCLUSION: This study describes and validates with robotic information a simple and reproducible preoperative planning method to determine femoral and tibial bone resection for medial UKA implantation using antero-posterior valgus stress knee radiographs, leaving a medial safety laxity of 2 mm. It represents a very valuable contribution to the understanding of UKA principles, which can serve to extend its indications and increase reproducibility of the surgical technique. LEVEL OF EVIDENCE: III. Retrospective cohort study.

Iron deficiency and supplementation in patients with heart failure: Results from the IRON-HF international survey.

AIMS: Iron deficiency (ID) is common in patients with heart failure (HF) and is associated with poor outcomes, regardless of anaemia status. Iron supplementation has been demonstrated to improve exercise capacity and quality of life in patients with HF with an ejection fraction <50% and ID. This survey aimed to provide data on real-world practices related to ID screening and management. METHODS AND RESULTS: We designed and distributed an online survey (23 questions) regarding ID screening and management in the HF setting. Overall, 256 cardiologists completed the survey (59.8% male, mostly between 30 and 50 years). The majority of physicians defined ID according to the most recent HF recommendations (98.4%) and reported screening for ID in more than half of their patients (68.4%). However, only 54.3% of the respondents performed periodic screening (every 6 months to 1 year). A total of 93.0% of participants prescribed and/or administered iron supplementation, using intravenous iron as the preferred method of administration (86.3%). After iron supplementation, 96.1% of the respondents reassessed ID, most frequently at 3-6 months (67.6%). Most physicians (93.8%) perceived ID as an underestimated comorbidity in HF. Cardiologists' age, training status, subspecialty and work setting (academic vs. non-academic hospitals) were associated with heterogeneity in the answers. CONCLUSIONS: The results of this survey highlight the need for more consistent strategies of ID screening and treatment for patients with HF.

Blood pressure response during exercise testing in individuals with and without hypertension: The value of the recovery phase.

BACKGROUND: Hypertension and exercise testing are essential for cardiovascular risk assessment. However, an exact description of blood pressure (BP) in patients with a hypertensive response during exercise (HRE), especially in the recovery phase is lacking. Herein, we aimed to analyse BP and heart rate during exercise testing and recovery in patients with an HRE. METHODS: 800 patients aged 17-90 with an HRE during a standardized bicycle ergometry test were recruited. The BP behaviour during exercise testing was correlated with clinical data. Furthermore, data were analysed according to the presence of pre-existent hypertension. RESULTS: Of the 800 patients included in this study 497 (62%) were previously diagnosed with hypertension. Analysis of covariance showed a significantly faster systolic (ß [95% CI] 8.0 [4.9-11.1]) and diastolic (2.4 [0.4-4.4]) BP recovery 3 min after maximal exercise in patients without hypertension in univariable models. These results remained robust in fully adjusted models taking into account age, sex, body mass index, cardiovascular disease, and antihypertensive treatment for systolic (5.3 [1.2-9.4]) and diastolic BP (4.5 [1.9-7.0]). Furthermore, patients with hypertension displayed higher systolic BP during maximal exercise in univariable (3.8 [0.1-7.5]) and fully adjusted (5.5 [1.1-10.0]) models. There was no difference in maximum diastolic BP between groups. CONCLUSION: In this large cohort study, patients without hypertension showed a faster systolic and diastolic BP recovery and lower maximal systolic BP compared to patients with hypertension. Overall, this study provides new insights into cardiovascular health during recovery phase.

Evaluating nutrition in advanced ovarian cancer: which biomarker works best?

BACKGROUND: Advanced epithelial ovarian cancer (OC) patients often present with malnutrition; however, the ideal nutritional evaluation tool is unclear. We aimed to evaluate the role of preoperative albumin, Prognostic Nutritional Index [PNI], neutrophil-to-lymphocyte ratio [NLR], and platelet-to-lymphocyte ratio [PLR] as independent predictors of severe postoperative complications and 90-day mortality in OC patients who underwent primary cytoreductive surgery to identify the ideal tool. METHODS: OC patients who underwent surgery at Mayo Clinic (2003-2018) were included; biomarkers were retrospectively retrieved and established cut-offs were utilized. Outcomes included severe complications (Accordion grade ≥ 3) and 90-day mortality. Univariate and multivariable logistic regression models were performed. Biomarkers were evaluated in separate models adjusted for age and American Society of Anesthesiologists (ASA) score for 90-day mortality, and adjusted for age, ASA score, stage, and surgical complexity for severe complications. RESULTS: Albumin <3.5 g/dL, PNI < 45, NLR > 6 and PLR ≥ 200 were univariately associated with 90-day mortality (all p < 0.05) in 627 patients that met inclusion criteria. Each marker remained significant in adjusted models with albumin having the highest OR: 6.04 [95% CI:2.80-13.03] and AUC (0.83). Univariately, PNI <45, NLR >6, and PLR ≥200 were significant predictors of severe complications(all p < 0.05), however failed to reach significance in adjusted models. Albumin was not associated with severe complications. CONCLUSION: All biomarkers were associated with 90-day mortality in adjusted models, with albumin being the easiest predictor to attain clinically; none with severe complications. Future research should focus less on methods of nutritional assessment and more on strategies to improve nutrition during OC tumor-directed therapy.

Phenotype clustering of hospitalized high-risk patients with COVID-19 - a machine learning approach within the multicentre, multinational PCHF-COVICAV registry.

IMTRODUCTION: The high-risk population of patients with cardiovascular (CV) disease or risk factors (RF) suffering from COVID-19 is heterogeneous. Several predictors for impaired prognosis have been identified. However, with machine learning (ML) approaches, certain phenotypes may be confined to classify the affected population and to predict outcome. This study aimed to phenotype patients using unsupervised ML technique within the International Postgraduate Course Heart Failure Registry for patients hospitalized with COVID-19 and Cardiovascular disease and/or RF (PCHF-COVICAV). MATERIAL AND METHODS: Patients from the eight centres with follow-up data available from the PCHF-COVICAV registry were included in this ML analysis (K-medoids algorithm). RESULTS: Out of 617 patients included into the prospective part of the registry, 458 [median age: 76 (IQR:65-84) years, 55% male] were analyzed and 46 baseline variables, including demographics, clinical status, comorbidities and biochemical characteristics were incorporated into the ML. Three clusters were extracted by this ML method. Cluster 1 (n = 181) represents mainly women with the least number of overall comorbidities and cardiovascular RF. Cluster 2 (n = 227) is characterized mainly by men with non-CV conditions and less severe symptoms of infection. Cluster 3 (n=50) mainly represents men with the highest prevalence of cardiac comorbidities and RF, more extensive inflammation and organ dysfunction with the highest 6-month all-cause mortality risk. CONCLUSIONS: The ML process has identified three important clinical clusters from hospitalized COVID-19 CV and/or RF patients. The cluster of males with severe CV disease, particularly HF, and multiple RF presenting with increased inflammation had a particularly poor outcome.

Effect of a Hypertensive Response During Exercise on Growth Rates of Aortic Diameters.

BACKGROUND: Aortic diameters are related to age, sex, and body size. There is a scarcity of data on the long-term sequelae of a hypertensive response to exercise (HRE) on aortic diameters. In this retrospective cohort study, we aimed to evaluate the relationship between the growth rates of the aorta in individuals with a HRE. METHODS: Our analysis included follow-up data of 649 patients recruited between January 2009 and December 2014 with a HRE. Participants with known connective tissue disease or a history of acute aortic syndrome were excluded. Sinus of Valsalva (SoV) and ascending aorta (AscAo) diameters were measured by transthoracic echocardiography using leading edge to leading edge convention at end-diastole. RESULTS: At baseline, median age, maximum systolic blood pressure (BP), body mass index (BMI), diameter of the SoV, and AscAo were 62 years, 208 mm Hg, 26.9 kg/m2, 35 mm, and 35 mm respectively. 32% of patients were female and 67% had hypertension. After a median follow-up of 7.1 years, mean yearly growth rates (±SD) of the SoV and AscAo were 0.09 (0.41) mm and 0.13 (0.56) mm, respectively. No significant associations were observed between growth rates of aortic diameters and maximum systolic and diastolic BP or when considering only individuals with a baseline diameter >40 mm. CONCLUSIONS: In this large cohort study, maximum systolic and diastolic BP during exercise showed no association with growth rates of aortic diameters. Furthermore, the mean growth rates of aortic diameters in this population were in line with growth rates in a normal population.

Pathophysiological Link and Treatment Implication of Heart Failure and Preserved Ejection Fraction in Patients with Chronic Kidney Disease.

Heart failure with preserved ejection fraction (HFpEF) results from a complex interplay of age, genetic, cardiac remodeling, and concomitant comorbidities including hypertension, obesity, diabetes, and chronic kidney disease (CKD). Renal failure is an important comorbidity of HFpEF, as well as a major pathophysiological mechanism for those patients at risk of developing HFpEF. Heart failure (HF) and CKD are intertwined conditions sharing common disease pathways; the so-called "kidney tamponade", explained by an increase in intracapsular pressure caused by fluid retention, is only the latest model to explain renal injury in HF. Recognizing the different phenotypes of HFpEF remains a real challenge; the pathophysiological mechanisms of renal dysfunction may differ across the HF spectrum, as well as the prognostic role. A better understanding of the role of cardiorenal interactions in patients with HF in terms of symptom status, disease progression, and prognosis remains essential in HF management. Historically, patients with HF and CKD have been scarcely represented in clinical trial populations. Current concerns affect the practical approach to HF treatment, and, in this context, physicians are frequently hesitant to prescribe and titrate both new and old treatments. Therefore, the extensive application of HF drugs in diverse HF subtypes with numerous comorbidities and different renal dysfunction etiologies remains a controversial matter of discussion. Numerous recently introduced drugs, such as sodium-glucose-linked transporter 2 inhibitors (SGLT2i), constitute a new therapeutic option for patients with HF and CKD. Because of their protective vascular and hormonal actions, the use of these agents may be safely extended to patients with renal dysfunction in the long term. The present review delves into the phenotype of patients with HFpEF and CKD from a pathophysiological perspective, proposing a treatment approach that suggests a practical stepwise algorithm for the proper application of life-saving therapies in clinical practice.

Venous Thromboembolism Management throughout the COVID-19 Era: Addressing Acute and Long-Term Challenges.

Background: COVID-19 increases the risk of venous thromboembolism (VTE) through a complex interplay of mechanisms collectively referred to as immunothrombosis. Limited data exist on VTE challenges in the acute setting throughout a dynamic long-term follow-up of COVID-19 patients compared to non-COVID-19 patients. The aim of the study was to investigate acute and long-term management and complications in VTE patients with and without COVID-19. Methods: A prospective, observational, single-center cohort study on VTE patients followed from the acute care stage until 24 months post-diagnosis. Results: 157 patients, 30 with COVID-19-associated VTE and 127 unrelated to COVID-19, were enrolled. The mean follow-up was 10.8 (±8.9) months. COVID-19 patients had fewer comorbidities (1.3 ± 1.29 vs. 2.26 ± 1.68, p < 0.001), a higher proportion of pulmonary embolism at baseline (96.7% vs. 76.4%, p = 0.01), and had a lower probability of remaining on anticoagulant therapy after three months (p < 0.003). The most used initial therapy was low-molecular-weight heparin in 130/157 cases, followed by long-term treatment with direct oral anticoagulants in 123/157. Two (6.7%) COVID-19 vs. three (2.4%) non-COVID-19 patients (p = 0.243) had major hemorrhagic events, all of them within the first three months. Four (3.1%) non-COVID-19 patients had VTE recurrence after six months. Three (2.4%) non-COVID-19 patients developed chronic thromboembolic pulmonary hypertension. There were no fatalities among patients with COVID-19, compared to a mortality of 12/127 (9.4%) in the non-COVID-19 subgroup (p = 0.027). Discussion: Our study offers a comprehensive overview of the evolving nature of VTE management, emphasizing the importance of personalized risk-based approaches, including a limited course of anticoagulation for most COVID-19-associated VTE cases and reduced-dose extended therapy for high-risk subsets.

Is the Number of Citations Related to the Study Methodology in Shoulder Arthroplasty Literature? A Bibliometric and Statistical Analysis of Current Evidence.

Background: We reviewed the shoulder arthroplasty (SA) literature to correlate citations, methodological characteristics and quality of most-cited articles in this field. We hypothesized that a greater number of citations would be found for high-quality clinical studies. Methods: We searched the Web of Knowledge database for the 50 most-cited articles about SA and collected author name, publication year, country of origin, journal, article type, level of evidence (LoE), subject of paper, type of arthroplasty and metrics (number of citations and citation rate). Coleman Methodology Score (CMS) was computed for clinical articles. Statistical analysis of variance and correlation coefficients were used to investigate the relationship between different variables. Results: Out of the selected 50 studies on SA, 26% were nonclinical. There were 15,393 citations overall (mean 307.8), with a mean 19.5 citations per year (range 48.3-6.7). Thirty or 60% of all articles were LoE IV. All studies were published between 1984 and 2011 in 8 journals. Reverse SA (RSA) was the most common subject (36% of studies). The United States was the country responsible for most contributions (50% of studies). CMS ranged from 81 to 38 (mean 59.6). RSA received the highest number of citations (P < .001), independently from country of origin (P = .137) and LoE (P = .723). CMS correlated with citation rate (r = 0.397; P = .013) and publication year (tau = 0.397; P = .013), but not with LoE (P = .204). Conclusion: In SA literature, citation rate positively correlates with methodological quality of a study, independently from publication country and LoE. Among most-cited papers, RSA is the most common standalone subject.

Impaired retinal micro-vascular function in patients with atrial fibrillation.

BACKGROUND: Cardiovascular (CV) risk factors and CV diseases, in particular heart failure, are strongly associated with impaired microvascular retinal endothelial function. Whether atrial fibrillation (AF) contributes to vascular dysfunction is not clear. Therefore, the aim of this study was to investigate the impact of AF on retinal microvascular function. METHODS: In this study, vascular function was measured non-invasively with flicker-light induced vasodilatation of retinal arterioles (FIDart%). Patients with a history of AF and risk factors for heart failure (HF) or heart failure (n = 69; age 67.9 ± 9.2 years, 71% male, 35% HFrEF, 56% paroxysmal, 25% persistent, 19% permanent AF), as well as age, sex and ejection fraction matched patients with absent history of AF (n = 66; age 63.4 ± 10.6 years, 67% male, 47% HFrEF) were included. Patients with AF were further divided into those with paroxysmal AF (in sinus rhythm - AFSR: n = 38, age 71.4 ± 9.2, 73% male), and those with AF at the time of the study visit. RESULTS: Retinal microvascular function was impaired in patients with AF compared to patients without AF (FIDart% 1.1% [0.3-2.8] vs. 2.7% [1.3-5.1], p < 0.001). Patients currently in AF have poorer retinal microvascular function (FIDart% 0.8% [0.1-1.9) compared to patients with a history of AF but currently in SR at the time of retinal function measurement (1.5% [0.6-4.9] p = 0.017). In patients with AF, impaired retinal vascular function was independently associated with larger left atrial volume (mean 49.8 ± 18.4), even after correction for confounding factors in different models (SCR = -0. 251 to -0.256, p = 0.035-0.01). CONCLUSIONS: AF in patients with heart failure is associated with impaired vascular function, even if currently in sinus rhythm. The association of retinal microvascular dysfunction with left atrial volume, a surrogate for elevated cardiac filling pressures, may further highlight the important interplay between the vasculature and elevated filling pressures in the development of AF.

Prolonging the stability of cetuximab (Erbitux®) and panitumumab (Vectibix®): An orthogonal assessment of physicochemical, biological and microbiological properties of original opened glass vials and diluted saline preparations.

The two anti-epidermal growth factor receptor monoclonal antibodies (mAbs) cetuximab and panitumumab are the pillars for the treatment of EGFR-positive, KRAS wild-type metastatic colorectal cancers. However, stability data of these mAbs are generally missing or incomplete. Here, we report for the first time an orthogonal analysis of the stability of cetuximab (Erbitux®) and panitumumab (Vectibix®), either undiluted vial leftovers or saline dilutions in polyolefin/polyamide infusion bags. All samples were stored at 2-8 °C protected from light, according to their summary of product characteristics (SmPCs). Alternatively, opened vials and preparations were maintained at 25 °C for 15 h, and then stored again at 2-8 °C protected from light to mimic a temporary interruption of the cold chain. Vial leftovers proved stable up to 180 days when stored according to their SmPCs, while compounded preparations in infusion bags maintained their physiochemical, biological and microbiological stability up to 30 days. Additionally, no changes were detected up to 30 days for the same samples undergoing a thermal excursion. Our results provide additional rationale to the SmPCs, crucial especially in the case of reassignment and pre-preparation of bags. This information will allow hospitals to achieve significant cost savings, and better organization of the entire therapeutic process.