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Abstract Urgent climate action, especially carbon emissions reduction, is required to achieve sustainable goals. Therefore, understanding the drivers of and predicting $$\hbox {CO}_2$$ emissions is a compelling matter. We present two global modeling frameworks—a multivariate regression and a Random Forest Regressor (RFR)—to hindcast (until 2021) and forecast (up to 2035) $$\hbox {CO}_2$$ emissions across 117 countries as driven by 12 socioeconomic indicators regarding carbon emissions, economic well-being, green and complexity economics, energy use and consumption. Our results identify key driving features to explain emissions pathways, where beyond-GDP indicators rooted in the Economic Complexity field emerge. Considering current countries’ development status, divergent emission dynamics appear. According to the RFR, a −6.2% reduction is predicted for developed economies by 2035 and a +19% increase for developing ones (referring to 2020), thus stressing the need to promote green growth and sustainable development in low-capacity contexts.

Introduction. Platinum-based chemotherapy represents the standard of care (SoC) for the first-line treatment of advanced urothelial carcinoma (mUC). The benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy was recently investigated. We performed an individual patient data (IPD) meta-analysis of phase 3 clinical trials comparing ICI-based treatments. Methods. A systematic literature search was conducted on the MEDLINE and CENTRAL databases. The results were filtered by including only reports on clinical trials or randomized clinical trials from 2018 to 2023, including 3047 patients from four clinical trials (EV302, CHECKMATE-901, IMVIGOR130, KEYNOTE-361). An IPD meta-analysis was performed by reconstructing IPD from Kaplan–Meier curves. The primary endpoints were overall survival (OS) and progression-free survival (PFS) of Pembrolizumab + EV compared to experimental arms of the other trials of immunotherapy + chemotherapy. Results. The OS analysis showed an advantage of IPD from EV302 vs. all the other trials. For EV302 vs. KEYNOTE-361, the HR was 0.51; for EV302 vs. IMVIGOR130, the HR was 0.47; and for EV302 vs. CHECKMATE-901, the HR was 0.66 (CI 95% 0.51–0.85). In the PFS analysis, the EV302 arm showed a statistically significant advantage compared to CHECKMATE-901 (HR 0.66) and versus IMVIGOR130 (HR 0.51). Limitations: By using reconstructed IPD curves, it was not possible to adjust patient-level covariates, and the heterogeneity of the included population may have affected the pooled results. Conclusions: The EV302 experimental arm showed better OS and PFS when compared to the other immunochemotherapy combinations. An immunochemotherapy combination strategy at the beginning of treatment in mUC seems to be superior in terms of OS and PFS compared to platinum-based chemotherapy alone. EV–Pembrolizumab resulted to have better outcomes compared to avelumab, rather than other immunochemotherapy combinations. However, given the heterogeneity of these studies, a longer follow up and prospective trials are needed to confirm these data.

Summary: Background: Glucocorticoids (GC) are potent entrainers of the circadian clock. However, their effects on biological rhythms in chronic human exposure have yet to be studied. Endogenous hypercortisolism (Cushing's Syndrome, CS) is a rare condition in which circadian disruption is sustained by a tumorous source of GC excess, offering the unique opportunity to investigate GC's chronic effects in vivo. Methods: In a 12-month prospective case–control multicentre trial, the daily fluctuations in the number of circulating peripheral blood mononuclear cells (PBMCs) and the time-specific expression of clock-related genes were analysed in a cohort of 68 subjects, 34 affected by CS and 34 matched controls. Cosinor mixed effects model, rhythmicity algorithms and machine learning techniques were applied to the multi-level dataset. Findings: Multiple, 5-point daily sampling revealed profound changes in the levels, amplitude, and rhythmicity of several PBMC populations during active CS, only partially restored after remission. Clock gene analyses in isolated PBMCs showed a significant flattening of circadian oscillation of CLOCK, PER1, PER2, PER3, and TIMELESS expression. In active CS, all methods confirmed a loss of rhythmicity of those genes which were circadian in the PBMCs of controls. Most, but not all, genes regained physiological oscillation after remission. Machine learning revealed that while combined time-course sets of clock genes were highly effective in separating patients from controls, immune profiling was efficient even as single time points. Interpretation: In conclusion, the oscillation of circulating immune cells is profoundly altered in patients with CS, representing a convergence point of circadian rhythm disruption and metabolic and steroid hormone imbalances. Machine learning techniques proved the superiority of immune profiling over parameters such as cortisol, anthropometric and metabolic variables, and circadian gene expression analysis to identify CS activity. Funding: The research leading to these results has received funding from the European Union in the context of the National Recovery and Resilience Plan, Investment PE8 – Project Age-It: “Ageing Well in an Ageing Society”. This resource was co-financed by the Next Generation EU [DM 1557 11.10.2022], the PRecisiOn Medicine to Target Frailty of Endocrine-metabolic Origin (PROMETEO) project (NET-2018-12365454) by the Italian Ministry of Health, and through internal funding to Sapienza University of Rome.

Introduction The allostatic load (AL) is a framework for conceptualising the physiological multisystemic impact of prolonged exposure to stress and its related side effects on mental health.Stress due to AL can influence the development and outcomes of cardiovascular diseases. AL increases the risk of coronary and peripherical artery diseases. AL emerges from the detection of emotional dimensions related to the disease, low psychosocial functioning and high rates of psychopathological signs in patients with hypertension or coronary heart disease.Method and analysis The primary endpoint of the PLAY-UP protocol is the implementation of a multidimensional model underlying the clinical treatment of patients with cardiovascular disease through the integration of medical and psychological clinical variables.PLAY-UP is a cohort study that will last for 24 months. 200 participants will be recruited and divided into three groups: early disease, midterm disease and long disease. All patients will undergo a clinical evaluation based on the detection of biological, medical and psychological indicators and variables. The evaluation battery will comprise three types of measurements: medical, psychological and pharmacological treatments. Clinical and psychological measurements will be processed in an integrated manner through the combination of all variables examined, elaborating the Allostatic Load Index from a longitudinal time perspective. The Allostatic Load Index will be calculated by measuring the z-score.Ethics and dissemination Ethical Committee Approval was obtained from CEtRA Abruzzo Region (IT) (ID 0461499/23). The results of the present project will be published in peer-reviewed journals, disseminated electronically and in print, and presented as abstracts and/or personal communications during national and international conferences.

In this article we present an overview of the SMASH hadronic transport approach that is applied for non-equilibrium dynamics of hadrons in heavy-ion collisions. We will give an overview about the ingredients of the approach and the applications for the dynamical description of heavy-ion collisions and for calculations of fundamental properties of the hadron gas. The main emphasis of the article will be the infrastructure for sustainable software development that we have developed over the last 10 years including extensive unit tests and continuous integration. We will also provide one section about the performance of the code and how it can be analyzed and improved in the future.

Abstract Background Breast cancer presents diverse molecular subtypes affecting treatment strategies. Human epidermal growth factor receptor 2 (HER2)-low, hormone receptor-positive (HR+) breast cancer poses a challenge due to limited targeted therapies. Current neoadjuvant treatment primarily utilizes chemotherapy, with conflicting results regarding efficacy in patients with HER2-low breast cancer. Trastuzumab deruxtecan (T-DXd) shows promise in HER2-low metastatic disease, and preliminary evidence suggests synergy with endocrine therapy. Objective This editorial explores the hypothesis that neoadjuvant T-DXd with or without endocrine therapy offers efficacy in the clinical management of HR+/HER2-low breast cancer. Methods We propose a phase II study with two treatment arms: T-DXd + letrozole and T-DXd alone. The primary endpoint is the radiological complete response rate. Secondary endpoints include pathological complete response rate, safety, event-free survival, and overall survival. Exploratory analyses will compare the arms to identify potential for optimizing treatment efficacy and minimizing side effects. Conclusions This study design allows for initial assessment of T-DXd with or without endocrine therapy in the treatment of HER2-low breast cancer. The findings may pave the way for personalized treatment strategies and inform future research, potentially leading to a chemotherapy-sparing approach.

Objective: To analyze data available in the literature regarding a possible prognostic value of the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) in prostate cancer (PCa) patients stratified in non-metastatic and metastatic diseases. Methods: A literature search process was performed following the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. In our meta-analysis, the pooled event rate estimated and the pooled hazard ratio were calculated using a random effect model. Results: Forty-two articles were selected for our analysis. The pooled risk difference for non-organ confined PCa between high and low NLR cases was 0.06 (95% confidence interval [CI]: −0.03–0.15) and between high and low PLR cases increased to 0.30 (95% CI: 0.16–0.43). In non-metastatic PCa cases, the pooled hazard ratio for overall mortality between high and low NLR was 1.33 (95% CI: 0.78–1.88) and between high and low PLR was 1.47 (95% CI: 0.91–2.03), whereas in metastatic PCa cases, between high and low NLR was 1.79 (95% CI: 1.44–2.13) and between high and low PLR was 1.05 (95% CI: 0.87–1.24). Conclusion: The prognostic values of NLR and PLR in terms of PCa characteristics and responses after treatment show a high level of heterogeneity of results among studies. These two ratios can represent the inflammatory and immunity status of the patient related to several conditions. A higher predictive value is related to a high NLR in terms of risk for overall mortality in metastatic PCa cases under systemic treatments.

Atrial fibrillation (AF) is a common cardiac arrhythmia that poses a significant risk of stroke and thromboembolic events. Anticoagulation therapy is essential for preventing stroke in patients with AF. An increasing number of people of all ages, including cardiac patients, approach physical activity as both a leisure-time exercise and a competitive sport. Therefore, patients at risk of AF are increasingly allowed to practice sports activities. Management of oral anticoagulant therapy (OAT) in these patients is extremely challenging because of the need to balance the risks and benefits of medications, considering both hemorrhagic (in case of trauma) and ischemic complications when the drugs are avoided. Official recommendations are limited for these patients and forbid sports that increase the risk of trauma and consequent bleeding in most cases. These recommendations are strongly influenced by the “traditional” management of OAT, which mainly involves coumarin derivatives. Non-vitamin K antagonist direct oral anticoagulants (DOACs), with their more favorable pharmacokinetic–pharmacodynamic profile than that of coumarin derivatives, may represent an opportunity to modify the approach to sports activity in patients with AF and indications for OAT. This study aimed to review the use of anticoagulants in athletes with AF, highlight their efficacy and safety, and provide practical considerations regarding their management.

Abstract: The therapeutic management of malocclusion in mixed dentition represents a crucial challenge in orthodontics. This study aims to illustrate the therapeutic approach adopted in a second class I division case, characterized by increased overjet (OVJ) and overbite (OVB), multiple dental rotations and contracted upper arch, by the use of preformed elastodontic guided eruption appliance (EGA). Materials and Methods: The initial clinical diagnosis revealed the need for early intervention to improve OVJ and correct the sagittal and vertical relationships of the den-to-alveolar process. A 10.5-year-old male patient with Division 1 Class II malocclusion was treated using two different EGA devices, both mixed and permanent dentition, for a total period of two years, with an average usage of about 10 hours per day. Results: The results obtained were significant, with complete resolution of malocclusion at the end of treatment. The active and passive forces generated by the shape of the device contributed to the correction of dental rotations and the improvement of verticality, reducing the OVB. Early use of such devices has been shown to significantly reduce the risks of dental trauma, while requiring low patient compliance and minimal psychological and psycho-social impact. Conclusions: The adoption of EGA has proven to be an effective therapeutic option in the early treatment of Division II malocclusion 1. The sequential approach with two different devices has helped to optimize the therapeutic results, reducing the need for more invasive orthodontic interventions at a later stage. However, it is essential to stress the importance of accurate diagnosis, appropriate planning and active collaboration of the patient to ensure the success of this interceptive approach.

Abstract A growing body of evidence suggests the role of male hypogonadism as a possible harbinger for poor clinical outcomes across hospitalized Covid-19 patients. Accordingly, we sought to investigate the impact of dysregulated hypothalamic-pituitary–gonadal axis on the severity of the clinical manifestations for hospitalized Covid-19 patients matched with healthy controls through a systematic review and meta-analysis. Databases were searched from inception to March 2022. A standardized mean difference (SMD) meta-analysis focused on hospitalized Covid-19 patients and healthy controls was developed for studies who reported total testosterone (TT) and luteinizing hormone (LH) levels at hospital admission. Overall, n = 18 series with n = 1575 patients between 2020 and 2022 were reviewed. A significant decrease in SMD of TT levels in Covid-19 patients compared to paired controls was observed (− 3.25 nmol/L, 95%CI − 0.57 and − 5.93). This reduction was even more consistent when matching severe Covid-19 patients with controls (− 5.04 nmol/L, 95%CI − 1.26 and − 8.82) but similar for Covid-19 survivors and non-survivors (− 3.04 nmol/L, 95%CI − 2.04 and − 4.05). No significant variation was observed for serum LH levels across studies. Patient related comorbidities, year of the pandemic, and total lymphocyte count were associated with the observed estimates. TT levels may be a useful serum marker of poor outcomes among Covid-19 patients. These findings may support the development of ad-hoc clinical trials in the Covid-19 risk-group classification and subsequent disease monitoring. The interplay between TT and immune response should be evaluated in future researches.

Background: Contrast-enhanced ultrasound (CEUS) is a diagnostic tool that is gaining popularity for its ability to improve overall diagnostic accuracy in bladder cancer (BC) staging. Our aim is to determine the cumulative diagnostic performance of CEUS in predicting preoperative muscle invasiveness using a comprehensive systematic review and pooled meta-analysis. Methods: A systematic review until October 2023 was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Patients with BC suspicion were offered CEUS before the transurethral resection of the bladder tumor (TURBT). The diagnostic performance of CEUS was evaluated based on non-muscle-invasive bladder cancer (NMIBC) vs. muscle-invasive bladder cancer (MIBC) confirmed at the final histopathological examination after TURBT. The outcomes were determined through pooled sensitivity, specificity, pooled positive likelihood ratio (PLR+), negative likelihood ratio (PLR−), and area under the summary receiver operating characteristic (SROC) along with their respective 95% confidence intervals (CI). Results: Overall, five studies were included. In these studies, a total of 362 patients underwent CEUS prior to TURBT. The pooled sensitivity and specificity were 0.88 (95% CI: 0.81–0.93) and 0.88 (95% CI: 0.82–0.92), respectively. SROC curve depicted a diagnostic accuracy of 0.94 (95% CI: 0.81–0.98). The pooled PLR+ and PLR− were 7.3 (95% CI: 4.8–11.2) and 0.14 (95% CI: 0.08–0.23), respectively. Conclusions: Our meta-analysis indicates that CEUS is highly accurate in the diagnosis and staging for BC. Beyond its accuracy, CEUS offers the advantage of being a cost-effective, safe, and versatile imaging tool.

The evaluation of landslide hazards in seismic areas is based on a deterministic analysis, which is unable to account for various uncertainties in the analysis process. This paper focuses on the probabilistic local seismic hazard analysis and extends the results to the landslide hazard analysis to consider both the uncertainties of the ground deformations and the strengths. The work studies the areas between Nibbiano and Sant’Erasmo hamlets in the Camerino municipality located in central Italy, where all constructions present evidence of damage caused by both the seismic sequence of 2016–2017 and the slope instability. An exhaustive geological and geophysical investigation has clarified the geological, geomorphological, and hydrogeological characteristics of the area, enabling a new characterization of material stress-strain behaviour. The study reveals that the low stiffness of the debris covers, and their fair degree of permeability contribute to potential instability scenarios triggered by both intense rainfall and the effects of strong earthquakes. The goal was to utilize the results to support local urban planning because in-depth knowledge of the possible evolutionary scenarios of the slopes is fundamental to the management of the degree of danger for structures, especially for people. Moreover, it was shown once again how a multi-source approach, with different investigation techniques, cannot be ignored for the study of the evolution of complex landslides.

The increasing diffusion of genetic analysis regarding the pathogenetic variants (PVs) of genes involved in DNA Damage Repair (DDR) mechanisms and the development of Poly ADP ribose polymerase (PARP) inhibitors (PARPis) led to the first valid precision medicine option tailored toward metastatic prostate cancer (mPC). The concept of anticipation in the systemic treatment of mPC was initially adopted for androgen receptor signaling inhibitors (ARSIs) to describe the expansion of their indications, from the setting of the late-stage second-line treatment of metastatic castration-resistant prostate cancer (mCRPC) to first-line therapy in selected cases. There is already mounting evidence in favor of the anticipation of PARPis in the first line of mCRPC therapy, and further evidence in favor of mHSPC is emerging. Many studies have demonstrated the synergism between ARSIs and PARP inhibitors. Recent discoveries regarding the crosstalk between the androgen receptor (AR) and DNA repair mechanisms are disconnecting the use of PARPis from genetic analysis. The new message emerging is that the combination of PARPis with ARSIs may work independently of DDR mutational status. As a matter of fact, most of the recent trials analyzing the combination of PARPis with abiraterone or enzalutamide as a first-line therapy enrolled mCRPC patients irrespective of their mutational status. The PROPEL trial concluded that the advantage of the combination was independent of PV status, despite a higher advantage being reported in the BRCA1/2 mutated subgroup. The MAGNITUDE trial, however, showed a significant advantage only in the DDR mutated subgroup, and the DDR non-mutated cohort was closed for further enrollment. The combination of PARPis with ARSIs represents a significant strategy with a view to the anticipation and intensification of care in mPC. However, it should not nullify the advantages of precision medicine linked to the genetic analysis of DDR genes.

Exosomes are extracellular nanovesicles (EV), that is, carriers of different biomolecules such as lipids, proteins, nucleic acids. Their composition and the fact that their release dramatically increases in cases of tumorigenesis open up different scenarios on their possible application to research into new biomarkers. The first purpose of the present review was to specifically analyze and compare different methodologies available for the use of exosomes in prostate cancer (PC). The most widely applied methodologies include ultracentrifugation techniques, size-based techniques, immunoaffinity capture-based techniques (mainly ELISA), and precipitation. To optimize the acquisition of exosomes from the reference sample, more techniques can be applied in sequence for a single extraction, thereby determining an increase in labor time and costs. The second purpose was to describe clinical results obtained with the analysis of PSA-expressing exosomes in PC; this provides an incredibly accurate method of discriminating between healthy patients and those with prostate disease. Specifically, the IC-ELISA alone method achieved 98.57% sensitivity and 80.28% specificity in discriminating prostate cancer (PC) from benign prostatic hyperplasia (BPH). An immunocapture-based ELISA assay was performed to quantify and characterize carbonic anhydrase (CA) IX expression in exosomes. The results revealed that CA IX positive exosomes were 25-fold higher in plasma samples from PC patients than in those from healthy controls. The analysis of PC-linked exosomes represents a promising diagnostic model that can effectively distinguish patients with PC from those with non-malignant prostatic disease. However, the use of exosome analysis in clinical practice is currently limited by several issues, including a lack of standardization in the analytical process and high costs, which are still too high for large-scale use.