Investigating Flow-Induced Corrosion of Magnesium in Ophthalmological Milieu

Although the impact of local fluid dynamics in the biodegradation of magnesium is well known, currently no studies in the literature address the degradation effects of ocular vitreous on bioresorbable devices made of magnesium, which could be developed as drug delivery carriers. The aim of this study was to investigate the flow-induced corrosion mechanism of magnesium in an ophthalmological environment for future applications in ophthalmic drug delivery. To achieve this, experimental and computational methods were combined. Specifically, a CFD model was employed to design experimental conditions that replicate the ocular flow-induced shear stress (FISS) on manufactured magnesium samples. Pure Mg samples were tested in a bioreactor system capable of imposing the ocular CFD calculated values of FISS on the Mg samples' surface by varying the pump flow rate. Optimal flow rates for a range of different FISS values specific to the ophthalmological fluid dynamics affecting the device were indeed determined before running the experiments. After conducting customized corrosion tests, morphological observations and profilometric maps of the eroded surfaces of Mg samples were obtained using scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). These maps were then post-processed for the parametric evaluation of corrosion rates. Pre-existing localized superficial defects did affect the final corrosion pattern. SEM images and CLSM data confirmed a uniform corrosion mechanism, with corrosion rates of 1.9, 2.7, and 3.4 mu m/day under different shear stress conditions (0, 0.01, and 0.032 Pa, respectively). More generally, uniform corrosion on pure Mg samples increased with higher FISS values, and at higher shear stress values (FISS = 0.032 Pa), a notable washing-out effect of the corrosion products was observed. The removal of corrosion products at higher shear stresses suggests that the dynamic ocular environment, influenced by saccadic movements, plays a significant role in the corrosion mechanism of pure magnesium. The corrosion rates determined in this study, in conjunction with clinical drug release requirements, are crucial for designing potential drug-release devices for ocular applications

Delayed gastric emptying after pancreatoduodenectomy: One complication, two different entities

Background: Delayed gastric emptying (DGE) is a common complication after pancreatoduodenectomy associated with a low complication burden but a prolonged hospital stay. The present study aimed to characterize DGE, with a particular focus on its subtypes and related predictors.Methods: A 2-center retrospective analysis was performed including consecutive pancreatoduodenectomy over 5 years. Primary delayed gastric emptying (pDGE) and secondary delayed gastric emptying (sDGE) were defined according to the presence of concomitant causing factors. Predictors of DGE, pDGE and sDGE were assessed through logistic regression.Results: Out of 1,170 patients considered, 188 developed delayed gastric emptying (16.1%). Most DGE (71.8%) were secondary. sDGE resolved later (P 1/4 .007), with hospital stay, duration of total parenteral nutrition, and of enteral nutrition being longer than for pDGE (all P < .005). Smoking status, total operative time, indication for surgery other than pancreatic cancer, estimated blood loss, and soft pancreatic texture were independent predictors of DGE. In the subgroup analysis of pDGE, smoking was the only independent predictor, whereas pylorus-preservation was a protective factor. Smoking, indication for surgery, estimated blood loss, soft gland texture, and main pancreatic duct diameter were independent predictors of sDGE.Conclusion: DGE after pancreatoduodenectomy consists of 2 different subtypes. The primary form re-solves earlier, and its occurrence might be reduced by pylorus preservation. For the secondary form, clinicians should focus on preventing and treating other trigger complications. The diagnosis of the DGE subtype has critical therapeutic implications and paves the way for further systematic studies.(c) 2022 Elsevier Inc. All rights reserved

Assessment of magnesium-based components for intraocular drug delivery by in vitro biocompatibility and drug-device interaction

The development of magnesium-based intraocular drug delivery devices holds significant promise for biomedical applications, particularly in treating wet age-related macular degeneration (AMD) using vascular endothelial growth factor inhibitors such as bevacizumab. Magnesium’s rapid degradation, which can be finely tuned to achieve the controlled release required for AMD treatment, along with its well-established biocompatibility and biodegradable properties, positioning it as an ideal material for these applications. The study aimed to evaluate magnesium’s potential as a carrier for ocular drug delivery systems by demontrating the stability of monoclonal antibodies, specifically bevacizumab, in the presence of magnesium corrosion products and the biocompatibility of these products with various cell lines, including murine fibroblasts (3T3), rat retinal Müller cells, and human retinal pigment epithelial cells (ARPE19). The stability of bevacizumab with pure magnesium (Mg) was investigated through an indirect enzyme-linked immunosorbent assay protocol, developed and customized for this specific aim. The biocompatibility of Mg corrosion products was assessed by toxicological evaluations through MTT and Trypan Blue Viability assays, along with cell cycle analysis. Results demonstrated no significant impact of Mg corrosion products on bevacizumab stability, with changes in mean values consistently below or equal to 10%. Furthermore, Mg extracts showed minimal cytotoxicity, as metabolic activity exceeded 80% across all cell lines, classified as Grade 0/1 cytotoxicity under ISO 10993-5 standards. Cell viability, proliferation, and morphology remained unaffected for up to 72 h of exposure. This study provides the first in vitro evaluation of bevacizumab’s stability in the presence of magnesium corrosion products and its biocompatibility with retinal cell lines, laying the foundation for future ophthalmic research and underscoring magnesium’s potential as a material for intraocular drug delivery systems

Six Drivers to Face the XXI Century Challenges and Build the New Healthcare System: "La Salute in Movimento" Manifesto

: The aging of the population, the burden of chronic diseases, possible new pandemics are among the challenges for healthcare in the XXI century. To face them, technological innovations and the national recovery and resilience plan within the European Union can represent opportunities to implement changes and renovate the current healthcare system in Italy, in an effort to guarantee equal access to health services. Considering such scenario, a panel of Italian experts gathered in a multidisciplinary Think Tank to discuss possible design of concepts at the basis of a new healthcare system. These ideas were summarized in a manifesto with six drivers for change: vision, governance, competence, intelligence, humanity and relationship. Each driver was linked to an action to actively move toward a new healthcare system based on trust between science, citizens and institutions

The Paleo-Indian Entry into South America According to Mitogenomes

Recent and compelling archaeological evidence attests to human presence 14.5 ka at multiple sites in South America and a very early exploitation of extreme high-altitude Andean environments. Considering that, according to genetic evidence, human entry into North America from Beringia most likely occurred 16 ka, these archeological findings would imply an extremely rapid spread along the double continent. To shed light on this issue from a genetic perspective, we first completely sequenced 217 novel modern mitogenomes of Native American ancestry from the northwestern area of South America (Ecuador and Peru); we then evaluated them phylogenetically together with other available mitogenomes (430 samples, both modern and ancient) from the same geographic area and, finally, with all closely related mitogenomes from the entire double continent. We detected a large number (N¼ 48) of novel subhaplogroups, often branching into further subclades, belonging to two classes: those that arose in South America early after its peopling and those that instead originated in North or Central America and reached South America with the first settlers. Coalescence age estimates for these subhaplogroups provide time boundaries indicating that early Paleo-Indians probably moved from North America to the area corresponding to modern Ecuador and Peru over the short time frame of 1.5 ka comprised between 16.0 and 14.6 ka

Risk factors associated with severe hospital burden of COVID-19 disease in Regione Lombardia: a cohort study.

BACKGROUND: Understanding the risk factors associated with hospital burden of COVID-19 is crucial for healthcare planning for any future waves of infection. METHODS: An observational cohort study is performed, using data on all PCR-confirmed cases of COVID-19 in Regione Lombardia, Italy, during the first wave of infection from February-June 2020. A multi-state modelling approach is used to simultaneously estimate risks of progression through hospital to final outcomes of either death or discharge, by pathway (via critical care or not) and the times to final events (lengths of stay). Logistic and time-to-event regressions are used to quantify the association of patient and population characteristics with the risks of hospital outcomes and lengths of stay respectively. RESULTS: Risks of severe outcomes such as ICU admission and mortality have decreased with month of admission (for example, the odds ratio of ICU admission in June vs March is 0.247 [0.120-0.508]) and increased with age (odds ratio of ICU admission in 45-65 vs 65 + age group is 0.286 [0.201-0.406]). Care home residents aged 65 + are associated with increased risk of hospital mortality and decreased risk of ICU admission. Being a healthcare worker appears to have a protective association with mortality risk (odds ratio of ICU mortality is 0.254 [0.143-0.453] relative to non-healthcare workers) and length of stay. Lengths of stay decrease with month of admission for survivors, but do not appear to vary with month for non-survivors. CONCLUSIONS: Improvements in clinical knowledge, treatment, patient and hospital management and public health surveillance, together with the waning of the first wave after the first lockdown, are hypothesised to have contributed to the reduced risks and lengths of stay over time

Dysregulation of splicing-related proteins in prostate cancer is controlled by FOXA1

Prostate cancer (PCa) is genomically driven by dysregulation of transcriptional networks involving the transcriptional factors (TFs) FOXA1, ERG, AR, and HOXB13. However, the role of these specific TFs in the regulation of alternative pre-mRNA splicing (AS), which is a proven therapeutic vulnerability for cancers driven by the TF MYC, is not described. Using transcriptomic datasets from PCa patients, we tested for an association between expression of FOXA1, ERG, AR, HOXB13, and MYC, and genes involved in AS - termed splicing-related proteins (SRPs), which have pleiotropic roles in RNA metabolism. We identified FOXA1 as the strongest predictor of dysregulated SRP gene expression, which was associated with PCa disease relapse after treatment. Subsequently, we selected a subset of FOXA1-binding and actively-transcribed SRP genes that phenocopy the FOXA1 dependency of PCa cells, and confirmed in vitro via knockdown and over-expression that FOXA1 regulates SRP gene expression. Finally, we demonstrated the persistence of a FOXA1-SRP gene association in treatment-relapsed castration-resistant PCa (CRPCa) patients. Our data demonstrate, for the first time, that FOXA1 controls dysregulated SRP gene expression, which is associated with poor PCa patient outcomes. Analogous to MYC-driven cancers, our findings implicate the therapeutic targeting of SRPs and AS in FOXA1-overexpressing PCa

A quantitative assessment of epidemiological parameters required to investigate COVID-19 burden

Solid estimates describing the clinical course of SARS-CoV-2 infections are still lacking due to under-ascertainment of asymptomatic and mild-disease cases. In this work, we quantify age-specific probabilities of transitions between stages defining the natural history of SARS-CoV-2 infection from 1965 SARS-CoV-2 positive individuals identified in Italy between March and April 2020 among contacts of confirmed cases. Infected contacts of cases were confirmed via RT-PCR tests as part of contact tracing activities or retrospectively via IgG serological tests and followed-up for symptoms and clinical outcomes. In addition, we provide estimates of time intervals between key events defining the clinical progression of cases as obtained from a larger sample, consisting of 95,371 infections ascertained between February and July 2020. We found that being older than 60 years of age was associated with a 39.9% (95%CI: 36.2–43.6%) likelihood of developing respiratory symptoms or fever ≥ 37.5 °C after SARS-CoV-2 infection; the 22.3% (95%CI: 19.3–25.6%) of the infections in this age group required hospital care and the 1% (95%CI: 0.4–2.1%) were admitted to an intensive care unit (ICU). The corresponding proportions in individuals younger than 60 years were estimated at 27.9% (95%CI: 25.4–30.4%), 8.8% (95%CI: 7.3–10.5%) and 0.4% (95%CI: 0.1–0.9%), respectively. The infection fatality ratio (IFR) ranged from 0.2% (95%CI: 0.0–0.6%) in individuals younger than 60 years to 12.3% (95%CI: 6.9–19.7%) for those aged 80 years or more; the case fatality ratio (CFR) in these two age classes was 0.6% (95%CI: 0.1–2%) and 19.2% (95%CI: 10.9–30.1%), respectively. The median length of stay in hospital was 10 (IQR: 3–21) days; the length of stay in ICU was 11 (IQR: 6–19) days. The obtained estimates provide insights into the epidemiology of COVID-19 and could be instrumental to refine mathematical modeling work supporting public health decisions