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During the reign of Christian IV Oldenburg (1588-1648), the Kingdom of Denmark-Norway reached the height of its influence in Northern Europe. Thanks to an impressive fleet, in the first part of the reign, the king reaffirmed Danish supremacy over the Baltic Sea (dominium maris Baltici) and supported Norwegian claims on the waters between the Scandinavian Peninsula and Iceland. However, by intervening in the Thirty Years’ War in 1625, the ambitious ruler fell prey to erroneous diplomatic and geopolitical choices, which jeopardized the very existence of the Kingdom of Denmark-Norway. Although Christian IV remains arguably the most iconic Danish monarch, his legacy is open to conflicting assessments: on the one hand, he brought the Dane-Norwegian state to the pinnacle of its prestige; on the other, his actions triggered the subsequent decline of Denmark and the rise of the Swedish Empire.

BackgroundSince the beginning of the SARS-CoV-2 pandemic, over 550 million people have been infected worldwide. Despite these large numbers, the long-term pulmonary consequences of COVID-19 remain unclear.AimsThe aim of this single-center observational cohort study was to identify and characterize pulmonary sequelae of COVID-19 at 12 months from hospitalization and to reveal possible predictors for the persistence of long-term lung consequences.MethodsBased on the persistence or absence of radiological changes after 12 months from hospitalization, the whole population was categorized into NOT-RECOVERED (NOT-REC) and RECOVERED (REC) groups, respectively. Clinical and pulmonary function data tests and clinical data were also collected and compared in the two groups. In the NOT-REC group, high resolution computed tomography (HRCT) images were semiquantitatively scored analyzing ground-glass opacities (GGO), interstitial thickening (IT), consolidations (CO), linear and curvilinear band opacities, and bronchiectasis for each lung lobe. Logistic regression analyses served to detect the factors associated with 12-month radiological consequences.ResultsOut of the 421 patients followed after hospitalization for SARS-CoV-2 pneumonia, 347 met inclusion and exclusion criteria and were enrolled in the study. The NOT-REC patients (n = 24; 6.9%) were significantly older [67 (62–76) years vs. 63 (53–71) years; p = 0.02], more frequently current smokers [4 (17%) vs. 12 (4%); p = 0.02], and with more severe respiratory failure at the time of hospitalization [PaO2/FiO2 at admission: 201 (101–314) vs. 295 (223–343); p = 0.01] compared to REC group (n = 323; 93.1%). On multivariable analysis, being a current smoker resulted in an independent predictor for lung sequelae after 12 months from hospitalization [5.6 OR; 95% CI (1.41–22.12); p = 0.01].ConclusionAfter 12 months from hospital admission, a limited number of patients displayed persistent pulmonary sequelae with minimal extension. Being a current smoker at the time of SARS-CoV-2 infection is an independent predictive factor to lung consequences, regardless of the disease severity.

Background: Improved skin appearance is closely linked to higher self‐esteem, favorable first impressions, and enhanced quality of life, with skincare products often being formulated with biostimulatory and regenerative ingredients to both enhance skin health and provide psychological benefits. Certain components, such as phospholipids and botanicals, may not only improve skin quality, but also impact mood, romantic bonding, and sexual attraction. Aims: To assess whether a novel topical skin care product formulated with a proprietary combination of proteins, lipids, and botanical derivatives, can potentially result in a robust psycho‐social‐dermatological benefit via modulation epidermal oxytocin and pheromonal pathways. Patients/Methods: In this single‐center prospective, randomized, controlled, double‐blinded study, 40 female subjects were randomly assigned to use of either active novel skincare products, or placebos, for 4–8 weeks. Skin assessments, standardized photography, first impression ratings, and questionnaires on confidence and sexual satisfaction were conducted. Results: Thirty‐nine subjects completed the study and demonstrated a statistically significant improvement in skin quality following 4 and 8 weeks of use, with improvements of greater magnitude demonstrated with a longer duration of use. Product users projected a better first impression and appeared on average 3 years younger than their actual age, with 86% of subjects reporting increased confidence. Product users found random people of the opposite sex to be more attractive 88% of the time and reported improvement in sexual satisfaction in 90% of the categories. Conclusions: The use of this novel topical product culminated in statistically significant improvements in skin quality, confidence, sexual relationship satisfaction, perceived attractiveness, and youthfulness, highlighting its potential in anti‐aging and mood enhancement. [ABSTRACT FROM AUTHOR]

Bacterial infections are a common complication in patients with decompensated liver cirrhosis. The complex landscape of cirrhosis, characterized by immune paralysis and an exhausted response to exogenous triggers, explains the higher prevalence of such infections, particularly in advanced disease stages. In clinical practice, the onset of a bacterial infection can lead to further deterioration of hepatic and extra-hepatic function, potentially resulting in acute decompensation or acute-on-chronic liver failure. This has significant clinical implications, particularly for patients awaiting a transplant. In this review, we will discuss the latest evidence on the diagnosis and therapy of bacterial infections in patients with decompensated cirrhosis. Additionally, we will analyze the impact of bacterial infections in the context of liver transplantation, discussing debated topics such as the timing of transplantation in patients with infections, potential implications for prioritization, effects on post-operative recovery, grafts, and patient survival. [ABSTRACT FROM AUTHOR]

This study investigates the prevalence and patterns of transmitted drug resistance mutations (TDRMs) and HIV-1 subtypes among antiretroviral therapy (ART) naïve individuals in Veneto, Italy, from 2017 to 2024. This research aims to understand the dynamic landscape of TDRMs and HIV-1 genetic diversity to inform treatment strategies effectively. We included all adult ART-naïve people with HIV (PWH) from seven infectious disease units in Veneto, Italy. We collected the genotypic resistance testing conducted to predict drug susceptibility and subtype distribution using the Stanford HIVdb algorithm. We included 762 PWH, showing a slight but statistically significant decline in the B subtype among Italian PWH (p = 0.045) and an increase in non-B subtypes among foreigners, though it was not statistically significant (p = 0.333). The most frequent mutations were in Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs), especially in non-B subtypes, with a notable rise from 10.7% in 2017–2019 to 15.5% in 2020–2024. Notably, TDRMs were consistently detected, highlighting an ongoing challenge despite the stable prevalence observed over the years. In addition, the data revealed a concerning rise in mutations against newer drug classes, such as integrase inhibitors. Conclusively, the study underscores the necessity of continuous surveillance of HIV subtypes and resistance patterns to adapt ART regimens optimally. Despite the stable levels of drug resistance, the emergence of resistance against newer drugs necessitates ongoing vigilance and possible adjustment in treatment protocols to enhance clinical outcomes and manage HIV drug resistance effectively. [ABSTRACT FROM AUTHOR]

Objectives To evaluate polypharmacy, anticholinergic burden (ACB) and drug–drug interactions (DDIs) in people with four-class-resistant HIV (4DR-PWH). Methods We performed a cross-sectional study, including 4DR-PWH from the PRESTIGIO Registry taking at least one non-antiretroviral drug. Polypharmacy was defined as taking five or more non-antiretroviral drugs. ACB was calculated using the ACB scale: 0 = no AC effect, 1–2 = low/moderate risk, ≥3 = high AC risk. Participants' characteristics by ACB score were compared using the Kruskal–Wallis test, and Spearman's correlation coefficient was used to assess linear relationships. DDIs were evaluated using the Liverpool database. Results Overall, 172 4DR-PLWH were evaluated: 75.6% males, median age 49.9 years (IQR = 45.6–56), 62 (27.1%) on polypharmacy, 124 (72.1%) using a boosting agent and 72 (41.8%) with four or more antiretrovirals. Based on ACB, 128 (74.45%), 33 (19.2%) and 11 (6.4%) had a no, low/moderate and high AC risk, respectively. The most common AC drugs were β-blockers (12.2%), diuretics (8.7%) and antidepressants (8.7%). The high ACB was significantly related to the number of drugs/person (r  = 0.33, P  <   0.0001) and the number of clinical events (r  = 0.222, P  = 0.004). Overall, 258 DDIs were found between antiretrovirals and co-medications in 115 (66.8%) PWH, and 14 (8.1%) PWH received contraindicated drug combinations. Conclusions In 4DR-PWH, polypharmacy, DDIs and the proportion of people with moderate/high AC burden were high. In 4DR-PWH undetectability achievement and maintenance is the priority and use of boosted PIs is common. A strict collaboration (infectious diseases specialists, virologists, pharmacologists) is needed to limit the risk of ACB and DDIs and to explore the advantages of new antiretrovirals. [ABSTRACT FROM AUTHOR]

This study evaluated cryogels from albumin (ALB) and albumin–pectin (ALB:PEC) as carriers for pink pepper (Schinus terebinthifolius Raddi) essential oil. Cryogels were evaluated through infrared spectrophotometry, X-ray diffraction, scanning electron microscopy, thermogravimetric analysis, and differential scanning calorimetry. The bioactivity of the cryogels was analyzed by measuring their encapsulation efficiency (EE%), the antimicrobial activity of the encapsulated oil against S. aureus, E. coli, and B. cereus using the agar diffusion method; total phenolic content and antioxidant activity were analyzed by UV-vis spectrophotometry. The EE% varied between 59.61% and 77.41%. The cryogel with only ALB had the highest total phenolic content with 2.802 mg GAE/g, while the cryogel with the 30:70 ratio (ALB:PEC) presented a value of 0.822 mg GAE/g. A higher proportion of PEC resulted in a more significant inhibitory activity against S. aureus, reaching an inhibition zone of 18.67 mm. The cryogels with ALB and 70:30 ratio (ALB:PEC) presented fusion endotherms at 137.16 °C and 134.15 °C, respectively, and semicrystalline structures. The interaction between ALB and PEC increased with their concentration, as evidenced by the decreased intensity of the O-H stretching peak, leading to lower encapsulation efficiency. The cryogels obtained can be considered a suitable matrix for encapsulating pink pepper oil. [ABSTRACT FROM AUTHOR]

Background: Clinical trials and real-life studies have granted the efficacy and safety of dolutegravir and lamivudine (DTG/3TC) in naïve and experienced people living with HIV (PLWH), but there are no long-term data in elderly people. We herein describe our real-life cohort of PLWH who were ≥65 years of age (PLWH ≥ 65) who started or were switched to DTG/3TC, single-tablet regimen, or DTG plus 3TC. Methods: We considered laboratory/clinical parameter changes from the baseline to the last follow-up time point available for each person by the paired Wilcoxon test and analyzed factors associated with virological failure (VF) and discontinuation. Results: We included 112 PLWH with a median age of 66 (IQR: 65–70) years, 77.6% males; 84.8% of people had multimorbidity, 34.8% were on polypharmacy, and only 5.4% were naïve to treatment. Reasons to be switched to DTG/3TC were: abacavir removal (38.7%), treatment simplification (33.1%), and PI discontinuation (28.2%). The median treatment durability was 6 (IQR: 5.4–7) years. No significant changes were detected in metabolic, renal, immunological, or cardiovascular biomarkers during follow-up. HIV RNA undetectability was maintained in 104 (92.8%) individuals for whom follow-up evaluation was available. We observed eight discontinuations (two deaths, two VFs, two early intolerances, one significant weight gain, and one switch to long-acting therapy). No factors were significantly associated with VF or discontinuation. Conclusions: This is the first study on DTG/3TC in PLWH ≥ 65 with a follow-up longer than 5 years. DTG/3TC was found to be safe and effective, neutral on metabolic parameters, and with a low discontinuation rate for toxicity or VF.

Background/aimsUveal melanoma is the most common type of non-cutaneous melanoma and the most common ocular malignancy in the adult population, especially affecting Caucasians (98% of cases). Despite its low incidence rate, we have noted increasing incidence trends in recent years.MethodsWe analyzed uveal melanoma incidence data using the Canadian Cancer Registry (CCR) for 2011–2017 years. The data was examined using the International Classification of Diseases for Oncology, Third Edition, codes for all uveal melanoma subtypes. The data for 2011–2017 was then compared to previously published work by our research group for uveal melanoma incidence in Canada between 1992 and 2010 using the same methodology.ResultsBetween 2011 and 2017, 1,215 patients were diagnosed with uveal melanoma, 49% of whom were females. The percentage distribution of uveal melanoma between the sexes was similar between 1992–2010 and 2011–2017, whereby of the 2,215 diagnoses of uveal melanoma in 1992–2010, 47.9% were females. The change in the incidence rate for this cancer has doubled between 1992–2010 and 2011–2017, from 0.074 to 0.15 cases per million individuals per year. Our study documents that the Canadian 2011–2017 age-standardized incidence rate (ASIR) for uveal melanoma against the World Health Organization (WHO) 2000–2025 world population standard was 5.09 cases per million individuals per year (95% confidence interval, 4.73–5.44), as compared with the 1992–2010 rate of 3.34 cases per million individuals per year (95% confidence interval, CI 3.20 to 3.47).ConclusionThis work demonstrates an ongoing, steady increase in uveal melanoma incidence in Canada in recent years.

Summary: Background: While acute kidney injury (AKI) is a common complication in COVID-19, data on post-AKI kidney function recovery and the clinical factors associated with poor kidney function recovery is lacking. Methods: A retrospective multi-centre observational cohort study comprising 12,891 hospitalized patients aged 18 years or older with a diagnosis of SARS-CoV-2 infection confirmed by polymerase chain reaction from 1 January 2020 to 10 September 2020, and with at least one serum creatinine value 1–365 days prior to admission. Mortality and serum creatinine values were obtained up to 10 September 2021. Findings: Advanced age (HR 2.77, 95%CI 2.53–3.04, p

Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma characterized by a very poor prognosis when relapses occur after front-line therapy. Therefore, a major challenge for patients’ management remains the identification of markers associated with refractory and progressive disease. In this context, cancer autoantibodies are natural markers of disease onset and progression, useful to unveil novel therapeutic targets. Herein, we matched autoantibody profiling of alveolar RMS (ARMS) patients with genes under regulatory control of PAX3-FOXO1 transcription factor and revealed fibroblast growth factor 8 (FGF8) as a novel ARMS tumor antigen of diagnostic, prognostic, and therapeutic potential. We demonstrated that high levels of FGF8 autoantibodies distinguished ARMS patients from healthy subjects and represented an independent prognostic factor of better event-free survival. FGF8 was overexpressed in ARMS tumors compared to other types of pediatric soft tissue sarcomas, acting as a positive regulator of cell signaling. Indeed, FGF8 was capable of stimulating ARMS cells migration and expression of pro-angiogenic and metastasis-related factors, throughout MAPK signaling activation. Of note, FGF8 was found to increase in recurrent tumors, independently of PAX3-FOXO1 expression dynamics. Risk of recurrence correlated positively with FGF8 expression levels at diagnosis and reduced FGF8 autoantibodies titer, almost as if to suggest a failure of the immune response to control tumor growth in recurring patients. This study provides evidence about the crucial role of FGF8 in ARMS and the protective function of natural autoantibodies, giving new insights into ARMS biology and laying the foundations for the development of new therapeutic strategies.

Background: Recent in-vitro data have shown that the activity of monoclonal antibodies (mAbs) targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) varies according to the variant of concern (VOC). No studies have compared the clinical efficacy of different mAbs against Omicron VOC. Methods: The MANTICO trial is a non-inferiority randomised controlled trial comparing the clinical efficacy of early treatments with bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab in outpatients aged 50 or older with mild-to-moderate SARS-CoV-2 infection. As the patient enrolment was interrupted for possible futility after the onset of the Omicron wave, the analysis was performed according to the SARS-CoV-2 VOC. The primary outcome was coronavirus disease 2019 (COVID-19) progression (hospitalisation, need of supplemental oxygen therapy, or death through day 14). Secondary outcomes included the time to symptom resolution, assessed using the product-limit method. Kaplan-Meier estimator and Cox proportional hazard model were used to assess the association with predictors. Log rank test was used to compare survival functions. Results: Overall, 319 patients were included. Among 141 patients infected with Delta, no COVID-19 progression was recorded, and the time to symptom resolution did not differ significantly between treatment groups (Log-rank Chi-square 0.22, p 0.90). Among 170 patients infected with Omicron (80.6% BA.1 and 19.4% BA.1.1), two COVID-19 progressions were recorded, both in the bamlanivimab/etesevimab group, and the median time to symptom resolution was 5 days shorter in the sotrovimab group compared with the bamlanivimab/etesevimab and casirivimab/imdevimab groups (HR 0.53 and HR 0.45, 95% CI 0.36–0.77 and 95% CI 0.30–0.67, p

The present article aims to provide a comprehensive overview of the state of the art of legal science on crowdfunding and to lay the foundation for the understanding of some of its key concepts, facilitating the development of future legal research. This paper demonstrates that legal scholarship seems to not take full comparative advantage of the fact that many concerns are common across jurisdictions, such as encouraging SME development through access to risk capital or ensuring the protection of the unsophisticated investor. It also shows that scholarship and legislative efforts, predominantly in the US and the EU, are most often focused on investment crowdfunding and that these efforts usually attempt to define the obligations of the crowdfunding service provider, striking a balance between stimulating access to risk capital for start-ups and scaling up the crowdfunding business while, at the same time, protecting investors - in particular the unsophisticated ones. Even though it is challenging to legally define specific crowdfunding services, the commonly used typology of crowdfunding is found to be meaningful in a legal context, as it denotes the applicable legal framework. Considering that there is a correlation between the clarity of regulation in a country and the volume of crowdfunding, and given that crowdfunding is growing as both a method of finance and as a business, the time is ripe for legal scholars to direct their attention to the field. In doing so, they assist the actors in the market, the legislators, and the judiciary.