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In a randomized trial of pomalidomide plus dexamethasone with or without the immunostimulatory monoclonal antibody elotuzumab, the addition of elotuzumab doubled both the response rate and the duration of progression-free survival without increased toxic effects.

Simultaneously targeting other pathways could increase the activity of PD-1 blockade in lymphoid malignancies not sensitive to single-agent blockade. We explored the safety and efficacy of combined PD-1 and CTLA-4 or KIR blockade in patients with relapsed/refractory (R/R) lymphoid malignancies. This phase 1b trial enrolled adult patients with R/R classical Hodgkin lymphoma (cHL), non-Hodgkin lymphoma (NHL), or multiple myeloma (MM). Patients received nivolumab plus ipilimumab (nivo/ipi) or lirilumab (nivo/liri) until complete response (CR), progression, or unacceptable toxicity. The primary endpoint was safety and tolerability, while secondary endpoints included overall (ORR) and CR rates (CRR), progression-free and overall survival. Sixty-five patients were treated with nivo/ipi, and 72 with nivo/liri. Twenty-nine percent of patients experienced grade 3–4 treatment-related adverse events with nivo/ipi, and 15% with nivo/liri. In cHL, ORR was 74% for nivo/ipi and 76% for nivo/liri, CRRs were 23% and 24%, respectively. In B-NHL and T-NHL, ORR range was 9–22% and CRR was 0–6%. No patient with MM had an objective response. While both combinations were active in cHL, the toxicity of nivo/ipi was higher than expected from nivolumab alone. These data suggest no meaningful improvement in the efficacy of the combinations over single-agent nivolumab in the diseases studied.

Antibiotic-induced dysbiosis has been increasingly implicated in a range of pediatric outcomes, yet the concept remains variably defined and often inconsistently applied. The purpose of this review is to provide an overview and critical evaluation of the available data regarding the effects of early-life exposure to β-lactam antibiotics on the developing microbiome. We conducted a narrative review of experimental and epidemiological studies examining β-lactam exposure during pregnancy, the perinatal period, and early childhood was conducted. β-lactams induce reproducible alterations in microbial composition, diversity, and metabolic function, including decreases in Bifidobacterium and Lactobacillus and a relative increase in Enterobacteriaceae and other facultative anaerobes, especially in early life. Reduced microbial diversity and changed short-chain fatty acid-producing taxa often accompany these compositional changes. However, associations with immune, metabolic, and neurodevelopmental outcomes are heterogeneous and frequently confounded by indication host-related factors. Evidence for causality in humans remains limited despite strong mechanistic support from animal models. Current data support cautious interpretation, even though β-lactam-associated microbiome perturbations may contribute to disease susceptibility during vulnerable developmental windows. While mechanistic and longitudinal evidence continues to develop, antibiotic stewardship focused on appropriate indication and duration is still crucial.

Secondary dilated cardiomyopathy (DCM) refers to left ventricular dilation and impaired systolic function arising from identifiable extrinsic causes, such as ischemia, hypertension, toxins, infections, systemic diseases, or metabolic disorders. Unlike primary DCM, which is predominantly genetic, secondary DCM represents a diverse spectrum of pathophysiological mechanisms linked to external insults on myocardial structure and function. The increasing prevalence of conditions such as alcohol use disorder, chemotherapy-induced cardiotoxicity, and viral myocarditis underscores the need for heightened awareness and early recognition of secondary DCM. A comprehensive analysis of clinical trial data and observational studies involving secondary dilative cardiomyopathy was conducted, with a focus on mortality, symptom relief, and major adverse events. A systematic literature review was performed using databases, including PubMed, Embase, and ClinicalTrials.gov, following PRISMA guidelines for study selection. Data were extracted on patient demographics, etiology of dilation, trial design, outcomes, and follow-up duration. Advances in diagnostic modalities have refined the ability to identify underlying causes of secondary DCM. For example, high-sensitivity troponin and cardiac magnetic resonance imaging are pivotal in diagnosing myocarditis and differentiating it from ischemic cardiomyopathy. Novel insights into toxin-induced cardiomyopathies, such as those related to anthracyclines and immune checkpoint inhibitors, have highlighted pathways of mitochondrial dysfunction and oxidative stress. Treatment strategies emphasize the management of the causing condition alongside standard heart failure therapies, including RAAS inhibitors and beta-blockers. Emerging therapies, such as myocardial recovery protocols in peripartum cardiomyopathy and immune-modulating treatments in myocarditis, are promising in reversing myocardial dysfunction. Secondary DCM encompasses a heterogeneous group of disorders that require a precise etiological diagnosis for effective management. Timely identification and treatment of the underlying cause, combined with optimized heart failure therapies, can significantly improve outcomes. Future research focuses on developing targeted therapies and exploring the role of biomarkers and precision medicine in tailoring treatment strategies for secondary DCM.

Introduction: Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by significant autoantibodies, particularly targeting nuclear antigens. SLE pathogenesis involves genetic, environmental, and hormonal factors. The disease course includes flares and remission and involves various organs. Recent therapeutic progresses, including biologics, have improved management and prognosis, though the long-term impact of novel therapies remains to be determined. Biologics in SLE: Rituximab, the earliest B-cell-oriented biologic, binds CD20 and depletes CD20+ B cells, leading to remission in some SLE patients. Belimumab is a B-cell-activating factor (BAFF) inhibitor with a recent additional indication for lupus nephritis. The CALIBRATE and BLISS-BELIEVE studies investigated combinations of these drugs with conventional therapies, showing varied efficacy. Ocrelizumab and obinutuzumab, newer CD20-oriented SLE therapies, together with ofatumumab and veltuzumab, are also promising. The latest trials highlight their efficacy and safety. Anifrolumab, targeting type-I interferon receptors, was evaluated in the TULIP 1/2 trials. The ongoing TULIP LTE trial supports the long-term safety and efficacy of anifrolumab. Additionally, the IRIS Phase III trial is exploring anifrolumab for lupus nephritis, showing favorable renal responses. Tocilizumab and secukinumab are being assessed for SLE, with mixed outcomes. Several biologics targeting the C5 complement protein, together with immunomodulators and immunotherapeutics, are also under investigation for potential benefits in SLE. Discussion: Biologics in SLE target specific immune components, aiming to improve disease control and reduce the side effects of conventional therapy. However, trial outcomes vary due to factors like inclusion criteria and trial design. Conclusions: Biotechnology progress enables targeted biologic therapies for SLE, reducing disease activity and improving patients’ quality of life.

Background: Atrial Fibrillation (AF) is associated with a prothrombotic state and increased risk of ischemic stroke. Type 2 diabetes mellitus (T2DM) is a major cardiometabolic comorbidity in AF and independently increases thromboembolic risk. D-dimer is a well-established biomarker of coagulation activation and fibrin turnover, but the specific contribution of T2DM to D-dimer levels in AF remains insufficiently characterized in real-world cohorts. Methods: We conducted a retrospective, observational, single-center study including 300 adult patients with non-valvular AF evaluated at a tertiary university hospital. Patients were stratified according to the presence of T2DM (150 with T2DM and 150 without diabetes). Plasma D-dimer levels were compared between groups and analyzed across clinically relevant thresholds and CHA2DS2-VASc categories. Multivariable linear and logistic regression models were used to assess the independent association between T2DM and D-dimer levels after adjustment for demographic factors, comorbidities, renal function, prior stroke, CHA2DS2-VASc score components, and oral anticoagulation. Results: Patients with T2DM exhibited significantly higher D-dimer levels than non-diabetic patients (median 0.94 vs. 0.63 µg/mL FEU, p < 0.001). T2DM was independently associated with higher log-transformed D-dimer levels (adjusted β = 0.19, p < 0.001) and with increased odds of elevated D-dimer above both 0.5 µg/mL and 1.0 µg/mL thresholds. Across all CHA2DS2-VASc categories, patients with T2DM consistently showed higher D-dimer concentrations. Findings remained robust in sensitivity analyses restricted to anticoagulated patients. Conclusions: In patients with atrial fibrillation, type 2 diabetes mellitus is associated with increased coagulation activity as reflected by higher D-dimer levels, independent of clinical thromboembolic risk. These results support the concept of a diabetes-associated hypercoagulable AF phenotype and highlight the potential role of coagulation biomarkers in refining risk stratification.

Metro network systems play an important role in urban transportation but they are vulnerable to various risks and disruptions. Having a comprehensive understanding of these risks is essential for their operation. In this paper, we aimed to assess the operational robustness of the Bucharest metro system. We employed graph theory and concepts. Using available data specific to the Bucharest metro system operation, we analyzed the type of disruptions across metro lines and stations. As expected, the two subway lines that sub-cross the city center experienced the greatest number of disruptions. Several stations on Line M1, that sub-cross the central urban area, were found to be particularly vulnerable. In our analysis, the results are as follows: the robustness indicator for the metro network, rT, is 0.1538, and the effective graph conductance (CG) is 0.1. These reveal that the Bucharest metro network can withstand up to 45% of node failures before collapsing. This indicates moderate robustness, suggesting that while the network can handle specific disruptions, targeted improvements are necessary to enhance overall resilience.

In this study we consider correlated and simultaneous interventions regarding: i—the physical infrastructure (by crossover lines between the two tracks of a tram line), ii—the characteristics of the trams (by bi-directional trams), as well as iii—tactical and operative decisions of the line manager. How these interventions are reflected in the functional reliability of the tram line service is demonstrated for both cases of the current operation and for the case of overloads, respectively, for the case of the temporary degradation of circulation caused by random disruptive events. The theoretical analysis, generalizing findings regarding the effectiveness of solutions to improve functional reliability, is supplemented with quantitative evaluations related to certain situations of disruptions. The proposed solutions aim to increase the attractiveness of urban public transport. Even if the evaluations are focused mainly on the interests of the service quality perceived by the user, the beneficial consequences for the line manager (in terms of technical and commercial efficiency) are also addressed.

Background and Objectives: Heart failure is associated with high morbidity and mortality and linked with several pre-existing health conditions and risk factors. Early detection and prompt management in heart failure improves patient outcomes. Liver involvement is associated with heart failure disease progression, and hence liver biomarkers and liver fibrosis may have a prognostic impact. Several blood test based markers and scoring systems estimate liver fibrosis and hence can be useful prognostic tools. Materials and Methods: We retrospectively analyzed a series of 303 patients with decompensated heart failure in a city in western Romania over a period of 6 months. Several biochemical parameters were measured, the FIB-4 score was estimated and echocardiography was performed. Results for targeted variables are presented using descriptive statistics. Patients were analyzed based on their LVEF categories. Statistical analysis was based on ANOVA one-way tests for continuous variables and Chi-square tests for categorical variables. Pairwise comparisons were performed based on Bonferroni adjusted significance tests. The correlations between FIB-4 score, LVEF and NT-pro BNP in patients with and without diabetes and hypertension were explored using Spearman’s correlation coefficient. Result: Age, gender, NYHA class, death, history of (h/o) type 2 diabetes mellitus (T2DM), h/o coronary artery disease (CAD), h/o arrhythmias, sodium, potassium, creatinine, eGFR, uric acid, NT-pro BNP, left atrial volume, LDL, HDL, and TG were analyzed by LVEF categories using ANOVA one-way tests, Chi-square tests, and Bonferroni correction comparisons. We found a strong statistically significant correlation between each of NT-pro BNP, left atrial volume, LDL, and HDL with the LVEF categories. Discussion: Early detection of cardiac dysfunction leads to better management in patients with cardiovascular risk factors including diabetes and hypertension. High LDL and low HDL levels contribute to a reduction in left ventricular (LV) function. Available literature suggests the FIB-4 score as superior to other non-invasive markers of fibrosis. It utilizes the patient’s age, platelet count, AST, and ALT, which can be available retrospectively, making it an easy and inexpensive tool. FIB-4 score has a few limitations. Conclusions: Our study has shown a statistically significant positive correlation between severity categories of LVEF and FIB-4 score for heart failure patients with and without diabetes, and for heart failure patients with or without hypertension. We propose the implementation of FIB-4 score as a prognostic tool for heart failure.

Introduction: Diabetes mellitus (DM) has a millennia-long history, with early references dating back to ancient Egypt and India. However, it was not until the 20th century that the connection between diabetes and insulin was fully understood. The sequencing of insulin in the 1950s initiated the convergence of biotechnology and diabetes management, leading to the development of recombinant human insulin in 1982. This marked the start of peptide-based therapies in DM. Recombinant peptides for DM treatment: Numerous recombinant peptides have been developed since, starting with modified insulin molecules, with the aim of bettering DM management through fine-tuning the glycemic response to insulin. Peptide-based therapies in DM have expanded substantially beyond insulin to include agonists of Glucagon-like peptide-1 receptor and Glucose-dependent insulinotropic polypeptide receptor, glucagon receptor antagonists, and even peptides exerting multiple receptor agonist effects, for better metabolic control. Insulin pumps, continuous glucose monitoring, and automated insulin delivery systems: The development of modern delivery systems combined with real-time glucose monitoring has significantly advanced diabetes care. Insulin pumps evolved from early large devices to modern sensor-augmented pumps with automated shutoff features and hybrid closed-loop systems, requiring minimal user input. The second-generation systems have demonstrated superior outcomes, proving highly effective in diabetes management. Islet cell transplantation, organoids, and biological pancreas augmentation represent innovative approaches to diabetes management. Islet cell transplantation aims to restore insulin production by transplanting donor beta cells, though challenges persist regarding graft survival and the need for immunosuppression. Organoids are a promising platform for generating insulin-producing cells, although far from clinical use. Biological pancreas augmentation relies on therapies that promote beta-cell (re)generation, reduce stress, and induce immune tolerance. Further biotechnology-driven perspectives in DM will include metabolic control via biotechnology-enabled tools such as custom-designed insulin hybrid molecules, machine-learning algorithms to control peptide release, and engineering cells for optimal peptide production and secretion.