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Aim: To evaluate angiotensin II (Ang II) and Ang-(1-7) levels and the cytokine profile in patients hospitalized with mild coronavirus disease 2019 (COVID-19) and contrast them with patients with identical clinical conditions but treated with high doses of vitamin D (vitD). Methods: From the 218 patients recruited (ClinicalTrials.gov NCT04411446), 16 participated in this sub-study and were randomized to a single oral dose of 500,000 IU vitD (n = 10) or placebo (n = 6). Plasmatic Ang II and Ang-(1-7) levels were determined by radioimmunoassay and interleukins (ILs) 1, 6, 8, and 10 and tumor necrosis factor alpha (TNF-α) by enzyme-linked immunosorbent assay before and after treatment. Parallel, serum 25-hydroxyvitamin D3 (25-OH vitD) concentrations as vitD status was measured by a chemiluminescence immunoassay. Results: A trend towards an increase in Ang-(1-7) and a decrease in Ang II levels were observed in placebo- and vitD-treated COVID-19 patients compared to baseline values. There was no difference in Ang II and Ang-(1-7) levels between placebo- and vitD-treated COVID-19 patients. Similar results were obtained with ILs profile. COVID-19 patients showed an increase in the protective component of the RAS which was not improved by vitD treatment. Conclusions: VitD did not improve RAS disbalance in COVID-19. Notwithstanding, the authors visualize that acute treatment with high doses of vitD may show a trend to a decline in inflammatory ILs and an increase in protective markers. Finally, the authors would like to highlight the limitations of this preliminary study, namely the small number of patients and the use of a large single bolus dose of vitD rather than lower daily doses for extended periods with prolonged follow-up times. All these factors need special consideration in the designs of new vitD supplementation trials. All these factors need special consideration in the designs of new vitD supplementation trials (ClinicalTrials.gov identifier: NCT04411446).

Purpose: To analyze the presence of potentially pathogenic variants of 29 candidate genes known to cause spermatogenic failure (SPGF) in patients with non-obstructive azoospermia (NOA) who underwent testicular histology. Materials and Methods: Forty-eight patients with unexplained NOA referred to the Department of Transfusion Medicine and Transplantation Biology, University Hospital Center Zagreb, Zagreb, Croatia for testicular biopsy. They were divided into three groups: those who had cryptorchidism (n=9), those with varicocele (n=14), and those with idiopathic NOA (n=25). All included patients underwent blood withdrawal for next-generation sequencing (NGS) analysis and gene sequencing. Results: We found a possible genetic cause in 4 patients with idiopathic NOA (16%) and in 2 with cryptorchidism (22%). No pathogenic or possibly pathogenic mutations were identified in patients with varicocele. Variants of undetermined significance (VUS) were found in 11 patients with idiopathic NOA (44%), 3 with cryptorchidism (33%), and 8 patients with varicocele (57%). VUSs of the USP9Y gene were the most frequently as they were found in 14 out of 48 patients (29%). In particular, the VUS USP9Y c.7434+14del was found in 11 patients. They showed varied histological pictures, including Sertoli cellonly syndrome, mixed atrophy, and hypospermatogenesis, regardless of cryptorchidism or varicocele. No direct correlation was found between the gene mutation/variant and the testicular histological picture. Conclusions: Different mutations of the same gene cause various testicular histological pictures. These results suggest that it is not the gene itself but the type of mutation/variation that determines the testicular histology picture. Based on the data presented above, it remains challenging to design a genetic panel with prognostic value for the outcome of testicular sperm extraction in patients with NOA.

Many studies have reported that early interventions on language and early literacy skills are important for preventing later reading difficulties at primary school. The aim of the study is to assess the effectiveness of a 12-week intervention programme focused on enhancing pre-schoolers' language and early literacy skills. Two groups of children (ages 5-6) were involved in the study: the "Talk-group", who participated in the intervention programme, and the "Play-group", who followed the standard preschool curriculum. The children's early literacy skills were tested in two sessions six months apart, at the beginning and at the end of the last year of preschool. Data analysis showed that children achieved significantly higher scores in nonword repetition and lexical comprehension at the second assessment; however, only the children in the Talk-group produced significantly higher phonological awareness scores at the second session, i.e. after the intervention. Additional tests showed that the intervention programme was effective only in the case of more basic phonological awareness skills. The programme's potential for supporting early literacy development in preschool and for preventing long-term difficulties in reading are discussed.

Habitat restoration is becoming an increasingly prevalent tool in the armoury of marine conservation, particularly given the expanding interest in creating nature-based solutions to a changing climate. Seagrass restoration is a particular focus of increased numbers of projects and although there is a growing number of examples of successful seagrass restoration attempts, there remain extensive case studies of poor success or restoration failure from around the globe. To enable marine habitat restoration to happen at scale and make a genuine contribution to carbon sequestration rates globally, improved methods that are both practical and simple are required to foster higher rates of success and lower costs. Here, we present seven bottlenecks to achieving reliable seed-based seagrass restoration. In doing so, we also provide opportunities for practical and simple ways in which the knowledge gaps that underpin these bottlenecks can be filled. Seed collection needs to be easier and more efficient; the processing and storage of seeds more controlled; and germination and seedling survival more effective so that fewer seeds are required for more reliable planting. We conclude that further collaborative multidisciplinary science is required in all parts of the world to improve seagrass seed-based restoration through better incorporation of faunal and microbial ecology, more reliable modelling, improved reporting of restoration failures and a wider investigation of seed-based ecology beyond a handful of species.

ABSTRACT Objective To verify the involvement of the endocannabinoid system in the immunomodulatory profile of stem cells from human exfoliated deciduous teeth, in the presence or absence of TNF-α, and agonist and antagonists of CB1 and CB2. Methods Stem cells from human exfoliated deciduous teeth were cultured in the presence or absence of an agonist, anandamide, and two antagonists, AM251 and SR144528, of CB1 and CB2 receptors, with or without TNF-α stimulation. For analysis of immunomodulation, surface molecules linked to immunomodulation, namely human leukocyte antigen-DR isotype (HLA-DR), and programmed death ligands 1 (PD-L1) and 2 (PD-L2) were measured using flow cytometry. Results The inhibition of endocannabinoid receptors together with the proinflammatory effect of TNF-α resulted in increased HLA-DR expression in stem cells from human exfoliated deciduous teeth, as well as, in these cells acquiring an anti-inflammatory profile by enhancing the expression of PD-L1 and PD-L2. Conclusion Stem cells from human exfoliated deciduous teeth respond to the endocannabinoid system and TNF-α by altering key immune response molecules.

ABSTRACT Objective: This study investigated the nutritional status, 25-hydroxyvitamin D (25OHD), albumin and risk factors associated with complications in patients with foot and ankle fragility fractures. Subjects and methods: Prospective study, developed with patients who suffered fractures due to fragility of the foot and ankle (n = 108); the type of fractured bone, fracture mechanisms and classification were studied and also pseudoarthrosis, treatment, surgical dehiscence, anthropometry, 25OHD and albumin. The Chi-square or Fisher's exact test, Mann-Whitney and Kruskal-Wallis tests were used in the statistical analysis and the multiple logistic regression analysis was used to identify the risk factors associated with complications. Results: The factors that, together, were associated with treatment complications were the level of 25OHD (p = 0.0055; OR = 0.868 [1,152]; 95% CI = 0.786; 0.959 [1.043;1.272]) and diabetes (p = 0.0034; OR = 30,181; 95% CI = 3.087; 295.036). The factors that, together, were associated with the presence of any complication, were age (p = 0.0139; OR = 1.058; 95% CI = 1.011; 1,106) and 25OHD level (p = 0.0198; OR = 0.917; 95% CI = 0.852; 0.986). There was a complication probability above 0.40 associated with lower 25OHD levels (values below 20 ng/mL) and older age (over 50 years). Conclusion: Lower or abnormal levels of 25OHD were associated with pseudoarthrosis, and age and 25OHD were both risk factors for treatment complications in patients with foot and ankle fractures.

Guiding legislation and associated bureaucracy for the ethical review of clinical trials observational studies and food related research play an important role in the competitiveness of a nation in the face of tough global competition to attract sponsors and investigators. This is of particular relevance in the case of multicentre trials and multidisciplinary research. Accordingly, in this report we tried to gather in-depth knowledge of the current role and practices of ethics committees nationwide in both clinical and research settings. This mini-review aims to describe the formulation and organization of ethical committees in Italy in order to provide a focus for deliberations on ethical issues in medical and scientific research in line with human rights, as set out in the European Union charter. Furthermore, we evaluated the impact of an institution's ethical committee intervention on reducing the time required to obtain an opinion from Research Ethics Committees by guiding investigators in addressing ethical issues in their proposed studies.

Abstract Glioblastoma multiforme (GBM) is the most aggressive primary tumor of the central nervous system and the diagnosis is often dismal. GBM pharmacological treatment is strongly limited by its intracranial location beyond the blood–brain barrier (BBB). While Temozolomide (TMZ) exhibits the best clinical performance, still less than 20% crosses the BBB, therefore requiring administration of very high doses with resulting unnecessary systemic side effects. Here, we aimed at designing new negative temperature-responsive gel formulations able to locally release TMZ beyond the BBB. The biocompatibility of a chitosan-β-glycerophosphate-based thermogel (THG)-containing mesoporous SiO2 nanoparticles (THG@SiO2) or polycaprolactone microparticles (THG@PCL) was ascertained in vitro and in vivo by cell counting and histological examination. Next, we loaded TMZ into such matrices (THG@SiO2-TMZ and THG@PCL-TMZ) and tested their therapeutic potential both in vitro and in vivo, in a glioblastoma resection and recurrence mouse model based on orthotopic growth of human cancer cells. The two newly designed anticancer formulations, consisting in TMZ-silica (SiO2@TMZ) dispersed in the thermogel matrix (THG@SiO2-TMZ) and TMZ, spray-dried on PLC and incorporated into the thermogel (THG@PCL-TMZ), induced cell death in vitro. When applied intracranially to a resected U87-MG-Red-FLuc human GBM model, THG@SiO2-TMZ and THG@PCL-TMZ caused a significant reduction in the growth of tumor recurrences, when compared to untreated controls. THG@SiO2-TMZ and THG@PCL-TMZ are therefore new promising gel-based local therapy candidates for the treatment of GBM.

Electron spins in diamond allow magnetometry with high sensitivity, but the bandwidth in the microwave regime is limited to a narrow band around their resonance frequency. Here, the authors solve this problem by coupling the spins to a thin film of yttrium iron garnet, exploiting the non-linear spin-wave dynamics of the magnet.