Characterization of a Nanoparticle Drug Delivery System for the Treatment of Inflammation in Spinal Cord Injury

Spinal cord injury (SCI) results from a mechanical primary injury that is followed by a multifactorial secondary injury which worsens the clinical course. Persistent inflammation is a crucial event during the secondary injury. Indeed, microglia/macrophage respond to traumatic stimuli by adopting an activated phenotype, which has a dual role. An M1 phenotype, associated with harmful effects, is expressed very early and persists for a long time in the injured site, whereas M2, associated with a beneficial phenotype, has only a transient expression in a subacute phase of the trauma. This suggests that microglia/macrophage mediated inflammation is a crucial therapeutic target. Nanoparticles (NPs) are selectively engulfed by microglia/macrophage as part of their endocytic/phagocytic activity in removing foreign bodies. Microglia assume phagocytic activity after traumatic stimuli and this makes NPs an excellent tool for carrying drug to these cells. So, in order to counteract this deleterious pro-inflammatory response, we decided to maximize the efficacy of a well-known anti-inflammatory drug, minocycline, through a NPs delivery tool selectively targeted to microglia/macrophage. We developed and tested a new drug delivery nanocarrier (minocycline loaded in poly-ε-caprolactone NPs, PCL Mino) in vitro and in vivo. Specifically, we demonstrated a reduced activation of microglia/macrophage after PCL Mino treatment in vitro and a reduction of cells with phagocytic-like phenotype, up to 15 days tested in vivo. To clarify the involvement of the inflammatory response associated to microglia/macrophage in SCI progression, we treated SCI mice in acute and subacute phase. PCL Mino treatment, only when administered acutely after the damage, was able to ameliorate the locomotor activity up to 63 days post injury. Furthermore, we demonstrated that this treatment reduced M1 macrophages recruitment orchestrated by activated microglial cells via CCL2 chemokine in the damaged site, suggesting a deleterious effect in the early phase of the injury of these cells. In conclusion, this delivery tool represents a new hope for SCI treatment by showing several advantages compared to conventionally administered anti-inflammatory therapy, such as maximization of therapeutic efficiency and reduction of side effects. Furthermore, the potential of transfer to clinical practice is aided by the large clinical use of minocycline and the high biocompatibility of the proposed NPs

Microwave-assisted synthesis of TEMPO-labeled hydrogels traceable with MRI

Polymer functionalization strategies have recently attracted relevant attention for several applications in biomaterials science. In particular, technological advancements in medical imaging has focused on the design of polymeric matrices to improve non-invasive approaches and the diagnostic accuracy. In this scenario, the use of microwave irradiation of aqueous solutions containing appropriate combinations of polymers is gaining increasing interests in the synthesis of sterile hydrogels without using monomers, eliminating the need to remove unreacted species. In this study we developed a method for in situ fabrication of TEMPO-labeled hydrogel based on one pot microwave reaction that can then be tracked by magnetic resonance imaging (MRI) without using toxic compounds that could be hostile for the target tissue. Click chemistry was used to link TEMPO to the polymeric scaffold. In in vivo model, the system was able to preserve the TEMPO paramagnetic activity until 1 month after the hydrogel injection, showing a clear detectable signal on T1-weighted MRI with a longitudinal relaxivity value of 0.29 mM s-1, comparable to the value of 0.31 mM s-1 characteristic of TEMPO application. The uncleavable conjugation between the contrast agent and the polymeric scaffold is a leading point to record these results: the use of TEMPO only physically entrapped in polymeric scaffold did not show MRI traceability already after few hours. Moreover, the use of TEMPO-labeled hydrogels can also help to reduce the amount of animals sacrificed being a longitudinal non-invasive technique

Role of Etiology in Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Counterfactual Event-Based Mediation Analysis

Background: Whether the etiology of underlying liver disease represents a prognostic factor in patients with hepatocellular carcinoma (HCC) treated with lenvatinib is still a matter of debate. This study investigates whether the viral etiology of HCC plays a prognostic role in overall survival (OS). Methods: Data derived from a multicenter series of 313 HCC patients treated with lenvatinib between 2019 and 2022 were analyzed. Actuarial survival estimates were computed using the Kaplan–Meier method and compared with the log-rank test. We performed an event-based counterfactual mediation analysis to estimate direct (chronic inflammation and immunosuppression), indirect (tobacco smoking, alcohol use, illicit drug abuse with injections), and the total effect of viral etiology on OS. Results were expressed as hazard ratio (HR) and 95% CI. Results: Median OS was 21 months (95% CI: 20–23) in the group with other etiologies and 15 months (14–16) in the group with viral etiology (p p < 0.0001). No difference in terms of adverse event rate was observed between the two groups. Conclusions: Patients affected by HCC with nonviral etiology treated with lenvatinib exhibit longer survival than those with viral etiology. This finding may have relevance in the treatment decision-making process

Factors Associated With Severe Gastrointestinal Diagnoses in Children With SARS-CoV-2 Infection or Multisystem Inflammatory Syndrome

IMPORTANCE Severe gastrointestinal (GI) manifestations have been sporadically reported in children with COVID-19; however, their frequency and clinical outcome are unknown.OBJECTIVE To describe the clinical, radiological, and histopathologic characteristics of children with COVID-19 presenting with severe GI manifestations to identify factors associated with a severe outcome.DESIGN, SETTING, AND PARTICIPANTS A multicenter retrospective cohort study (February 25, 2020, to January 20, 2021) enrolled inpatient and outpatient children (aged &lt;18 years) with acute SARS-CoV-2 infection, confirmed by positive real-time reverse-transcriptase-polymerase chain reaction on nasopharyngeal swab or fulfilling the US Centers for Disease Control and Prevention criteria for multisystem inflammatory syndrome in children (MIS-C). The study was conducted by pediatricians working in primary care or hospitals in Italy participating in the COVID-19 Registry of the Italian Society of Pediatric Infectious Diseases.MAIN OUTCOMES AND MEASURES The occurrence of severe GI manifestations, defined by a medical and/or radiological diagnosis of acute abdomen, appendicitis (complicated or not by perforation and/or peritonitis), intussusception, pancreatitis, abdominal fluid collection, and diffuse adenomesenteritis requiring surgical consultation, occurring during or within 4 to 6 weeks after infection with SARS-CoV-2 infection. Logistic regression was used to estimate odds ratios (ORs) with 95% CIs of factors potentially associated with severe outcomes.RESULTS Overall, 685 children (386 boys [56.4%]; median age, 7.3 [IQR, 1.6-12.4] years) were included. Of these children, 628 (91.7%) were diagnosed with acute SARS-CoV-2 infection and 57 (8.3%) with MIS-C. The presence of GI symptoms was associated with a higher chance of hospitalization (OR, 2.64; 95% CI, 1.89-3.69) and intensive care unit admission (OR, 3.90; 95% CI, 1.98-7.68). Overall, 65 children (9.5%) showed severe GI involvement, including disseminated adenomesenteritis (39.6%), appendicitis (33.5%), abdominal fluid collection (21.3%), pancreatitis (6.9%), or intussusception (4.6%). Twenty-seven of these 65 children (41.5%) underwent surgery. Severe GI manifestations were associated with the child's age (5-10 years: OR, 8.33; 95% CI, 2.62-26.5; &gt;10 years: OR, 6.37; 95% CI, 2.12-19.1, compared with preschool-age), abdominal pain (adjusted OR [aOR], 34.5; 95% CI, 10.1-118), lymphopenia (aOR, 8.93; 95% CI, 3.03-26.3), or MIS-C (aOR, 6.28; 95% CI, 1.92-20.5). Diarrhea was associated with a higher chance of adenomesenteritis (aOR, 3.13; 95% CI, 1.08-9.12) or abdominal fluid collection (aOR, 3.22; 95% CI, 1.03-10.0).CONCLUSIONS AND RELEVANCE In this multicenter cohort study of Italian children with SARS-CoV-2 infection or MIS-C, 9.5% of the children had severe GI involvement, frequently associated with MIS-C. These findings suggest that prompt identification may improve the management of serious complications

Rationale and design of the CV-PREVITAL study: an Italian multiple cohort randomised controlled trial investigating innovative digital strategies in primary cardiovascular prevention

Introduction Prevention of cardiovascular disease (CVD) is of key importance in reducing morbidity, disability and mortality worldwide. Observational studies suggest that digital health interventions can be an effective strategy to reduce cardiovascular (CV) risk. However, evidence from large randomised clinical trials is lacking.Methods and analysis The CV-PREVITAL study is a multicentre, prospective, randomised, controlled, open-label interventional trial designed to compare the effectiveness of an educational and motivational mobile health (mHealth) intervention versus usual care in reducing CV risk. The intervention aims at improving diet, physical activity, sleep quality, psycho-behavioural aspects, as well as promoting smoking cessation and adherence to pharmacological treatment for CV risk factors. The trial aims to enrol approximately 80 000 subjects without overt CVDs referring to general practitioners’ offices, community pharmacies or clinics of Scientific Institute for Research, Hospitalization and Health Care (Italian acronym IRCCS) affiliated with the Italian Cardiology Network. All participants are evaluated at baseline and after 12 months to assess the effectiveness of the intervention on short-term endpoints, namely improvement in CV risk score and reduction of major CV risk factors. Beyond the funded life of the study, a long-term (7 years) follow-up is also planned to assess the effectiveness of the intervention on the incidence of major adverse CV events. A series of ancillary studies designed to evaluate the effect of the mHealth intervention on additional risk biomarkers are also performed.Ethics and dissemination This study received ethics approval from the ethics committee of the coordinating centre (Monzino Cardiology Center; R1256/20-CCM 1319) and from all other relevant IRBs and ethics committees. Findings are disseminated through scientific meetings and peer-reviewed journals and via social media. Partners are informed about the study’s course and findings through regular meetings.Trial registration number NCT05339841