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Biomaterials play an important role in the development of advancing three dimensional (3D) in vitro skin models, providing valuable insights for drug testing and tissue-specific modeling. Commercial materials, such as collagen, fibrin or alginate, have been widely used in skin modeling. However, they do not adequately represent the molecular complexity of skin components. On this regard, the development of novel biomaterials that represent the complexity of tissues is becoming more important in the design of advanced models. In this study, we have obtained aged human decellularized dermal extracellular matrix (dECM) hydrogels extracted from cadaveric human skin and demonstrated their potential as scaffold for advanced skin models. These dECM hydrogels effectively reproduce the complex fibrillar structure of other common scaffolds, exhibiting similar mechanical properties, while preserving the molecular composition of the native dermis. It is worth noting that fibroblasts embedded within human dECM hydrogels exhibit a behavior more representative of natural skin compared to commercial collagen hydrogels, where uncontrolled cell proliferation leads to material shrinkage. The described human dECM hydrogel is able to be used as scaffold for dermal fibroblasts in a skin aging-on-a-chip model. These results demonstrate that dECM hydrogels preserve essential components of the native human dermis making them a suitable option for the development of 3D skin aging models that accurately represent the cellular microenvironment, improving existing in vitro skin models and allowing for more reliable results in dermatopathological studies.

Cardiovascular diseases affect kidney function. The aim of this study was to investigate the possible associations between hemodynamic parameters and change in kidney function in individuals aged 75 years and older. Data on hemodynamics and blood and urine samples were collected at baseline and during one-year visits. Hemodynamics were split into two groups based on median values. Changes in the estimated glomerular filtration rate (eGFR) were investigated between low and high groups for each hemodynamic parameter using analysis of variance. Changes in the albumin–creatinine ratio (ACR) were examined as binary outcomes (large increase vs. stable) using logistic regression. The population consisted of 252 participants. Participants in the high central systolic blood pressure (cSBP) group had a greater decline in eGFR than participants in the low cSBP group (−6.3% vs. −2.7%, p = 0.006). Participants in the high aortic pulse wave velocity (aPWV) group had a greater decline in eGFR than those in the low aPWV group (−6.8% vs. −2.5%, p = 0.001). Other hemodynamic parameters were not associated with eGFR changes. Hemodynamics were not associated with changes in the ACR; aPWV and cSBP appear to be predictors for eGFR decline in older age; monitoring and treatment of elevated stiffness might be helpful in order to prevent kidney function decline.

Abstract Climate services are largely supported by climate reanalyses and by satellite Fundamental (Climate) Data Records (F(C)DRs). This paper demonstrates how the development and the uptake of F(C)DR benefit from radiance simulations, using reanalyses and radiative transfer models. We identify three classes of applications, with examples for each application class. The first application is to validate assumptions during F(C)DR development. Hereto we show the value of applying advanced quality controls to geostationary European (Meteosat) images. We also show the value of a cloud mask to study the spatio‐temporal coherence of the impact of the Mount Pinatubo volcanic eruption between Advanced Very High Resolution Radiometer (AVHRR) and the High‐resolution Infrared Radiation Sounder (HIRS) data. The second application is to assess the coherence between reanalyses and observations. Hereto we show the capability of reanalyses to reconstruct spectra observed by the Spektrometer Interferometer (SI‐1) flown on a Soviet satellite in 1979. We also present a first attempt to estimate the random uncertainties from this instrument. Finally, we investigate how advanced bias correction can help to improve the coherence between reanalysis and Nimbus‐3 Medium‐Resolution Infrared Radiometer (MRIR) in 1969. The third application is to inform F(C)DR users about particular quality aspects. We show how simulations can help to make a better‐informed use of the corresponding F(C)DR, taking as examples the Nimbus‐7 Scanning Multichannel Microwave Radiometer (SMMR), the Meteosat Second Generation (MSG) imager, and the Defense Meteorological Satellite Program (DMSP) Special Sensor Microwave Water Vapor Profiler (SSM/T‐2).

Background: Insulin, secreted from pancreatic islets of Langerhans, is of critical importance in regulating glucose homeostasis. Defective insulin secretion and/or the inability of tissues to respond to insulin results in insulin resistance and to several metabolic and organ alterations. We have previously demonstrated that BAG3 regulates insulin secretion. Herein we explored the consequences of beta-cells specific BAG3 deficiency in an animal model. Methods: We generated a beta-cells specific BAG3 knockout mouse model. Glucose and insulin tolerance tests, proteomics, metabolomics, and immunohistochemical analysis were used to investigate the role of BAG3 in regulating insulin secretion and the effects of chronic exposure to excessive insulin release in vivo. Results: Beta-cells specific BAG3 knockout results in primary hyperinsulinism due to excessive insulin exocytosis finally leading to insulin resistance. We demonstrate that resistance is mainly muscle-dependent while the liver remains insulin sensitive. The chronically altered metabolic condition leads in time to histopathological alterations in different organs. We observe elevated glycogen and lipid accumulation in the liver reminiscent of non-alcoholic fatty liver disease as well as mesangial matrix expansion and thickening of the glomerular basement membrane, resembling the histology of chronic kidney disease. Conclusion: Altogether, this study shows that BAG3 plays a role in insulin secretion and provides a model for the study of hyperinsulinemia and insulin resistance.

Abstract Background The risk for symptomatic COVID-19 requiring hospitalization is higher in the older population. The course of the disease in hospitalised older patients may show significant variation, from mild to severe illness, ultimately leading to death in the most critical cases. The analysis of circulating biomolecules involved in mechanisms of inflammation, cell damage and innate immunity could lead to identify new biomarkers of COVID-19 severity, aimed to improve the clinical management of subjects at higher risk of severe outcomes. In a cohort of COVID-19 geriatric patients (n= 156) who required hospitalization we analysed, on-admission, a series of circulating biomarkers related to neutrophil activation (neutrophil elastase, LL-37), macrophage activation (sCD163) and cell damage (nuclear cfDNA, mithocondrial cfDNA and nuclear cfDNA integrity). The above reported biomarkers were tested for their association with in-hospital mortality and with clinical, inflammatory and routine hematological parameters. Aim of the study was to unravel prognostic parameters for risk stratification of COVID-19 patients. Results Lower n-cfDNA integrity, higher neutrophil elastase and higher sCD163 levels were significantly associated with an increased risk of in-hospital decease. Median (IQR) values observed in discharged vs. deceased patients were: 0.50 (0.30-0.72) vs. 0.33 (0.22-0.62) for n-cfDNA integrity; 94.0 (47.7-154.0) ng/ml vs. 115.7 (84.2-212.7) ng/ml for neutrophil elastase; 614.0 (370.0-821.0) ng/ml vs. 787.0 (560.0-1304.0) ng/ml for sCD163. The analysis of survival curves in patients stratified for tertiles of each biomarker showed that patients with n-cfDNA integrity < 0.32 or sCD163 in the range 492-811 ng/ml had higher risk of in-hospital decease than, respectively, patients with higher n-cfDNA integrity or lower sCD163. These associations were further confirmed in multivariate models adjusted for age, sex and outcome-related clinical variables. In these models also high levels of neutrophil elastase (>150 ng/ml) appeared to be independent predictor of in-hospital death. An additional analysis of neutrophil elastase in patients stratified for n-cfDNA integrity levels was conducted to better describe the association of the studied parameters with the outcome. Conclusions On the whole, biomarkers of cell-free DNA integrity, neutrophil and macrophage activation might provide a valuable contribution to identify geriatric patients with high risk of COVID-19 in-hospital mortality.

Objective: The aim of the current review is to summarize the available evidence to aid clinicians in the surveillance, treatment and follow-up of the different primary tumors developed by patients diagnosed with von Hippel-Lindau (VHL) syndrome. Methods: A non-systematic narrative review of original articles, meta-analyses, and randomized trials was conducted, including articles in the pre-clinical setting to support relevant findings. Results: VHL disease is the most common rare hereditary disorder associated with clear cell renal cell carcinoma. Affected individuals inherit a germline mutation in one VHL allele, and any somatic event that disrupt the other allele can trigger mutations, chromosomal rearrangements, or epigenetic regulations leading to oncogenesis. From a clinical perspective, patients continuously develop multiple primary tumors. Conclusion: Because VHL is considered a rare disease, very limited evidence is available for diagnosis, surveillance, active treatment with local or systemic therapy and follow-up.

Abstract Background Pulmonary arterial hypertension is a progressive, debilitating condition characterized by increased resistance in the pulmonary arterial circulation. Current treatments for pulmonary arterial hypertension include endothelin receptor antagonists such as bosentan, sitaxentan, ambrisentan, macitentan, and oral prostacyclin receptor agonists such as selexipag. Endothelin receptor antagonists have been associated with liver injury, while hepatotoxicity was not reported for selexipag. Although genetic variability has been indisputably associated with variability in drug response, no study has been designed until now to assess its effects on the pharmacokinetics of endothelin receptor antagonists or selexipag. Case presentation We report the case of a 58-year-old female Caucasian patient with a dramatic increase in plasma levels of transaminases after treatment with macitentan and selexipag, drugs whose risk of causing liver injury has so far been considered limited. After therapy discontinuation, plasma levels of transaminases returned to baseline, thus suggesting a role of these drugs in the observed hepatotoxicity. After pharmacological counseling, we decided to introduce ambrisentan for the patient’s treatment. After 7 months of treatment, no liver injury has been reported. To evaluate the role of genetic factors in the observed hepatotoxicity, we genotyped the patient for single-nucleotide polymorphisms previously associated with macitentan, ambrisentan, or selexipag metabolism. We found a genetic profile associated with a poor metabolizer (PM) phenotype for CYP2C8 and CYP2C9, key enzymes for elimination of both macitentan and selexipag. The reported results suggest that an allelic profile associated with low activity for CYP2C8 and CYP2C9 enzyme could be a potential risk factor for macitentan and selexipag-induced liver injury and could provide a possible marker for early identification of subjects at higher risk of developing hepatotoxicity. Conclusions A multidisciplinary approach based on clinical evaluation, as well as pharmacological counseling and evaluation of the patient’s genetic profile, might be useful for identification of patients with a high chance of drug-induced liver injury, avoiding unnecessary risks in therapy selection and prescription.

Abstract Background Fear of falling (FoF) is an important risk factor for falls among older people. The objectives of our investigations were: a.) to present characteristics of older community-dwelling (CD) fallers with persistent or transient FoF (P-FoF or T-FoF) over 12 months, and b.) to investigate clinical predictors of P-FoF and T-FoF and c.) to explore differences between P-FoF and T-FoF. Methods Our series consisted of 389 older people reporting a fall or injurious fall at baseline and during 24 months follow-up participating in a multicenter prospective study. T-FoF was defined as participants reported “not at all” at baseline and “somewhat/fairly/very concerned” at follow-up, or “not at all” at follow-up, and “somewhat/fairly/very concerned” at baseline, and P-FoF was defined as participants answered “somewhat/fairly/very concerned” in both assessments at baseline and at follow-up. The association between risk factors and T-FoF or P-FoF was investigated by logistic regression analysis. Results The mean age of fallers in our sample was 79.0 years (SD 6.0), and 54.2% were females. Out of 389 older adults with a fall history at baseline, 83 participants (21.3%) did not report any FoF over time, P-FoF and T-FoF were observed in 42.7% and 35.9% of participants, respectively. After adjusting for potential confounders (e.g. age, gender), osteoporosis (OR = 2.04, 95%CI = 1.03–4.05) and impaired physical performance (OR = 2.38, 95%CI = 1.12–5.03) were significant predictors of T-FoF vs No-FoF. Osteoporosis (OR = 2.68, 95%CI = 1.31–5.48), depressive symptoms (OR = 3.54, 95%CI = 1.23–10.1) and living alone (OR = 2.44, 95%CI = 1.17–5.06) were significantly associated with P-FoF vs No-FoF. When comparing T-FoF and P-FoF, female gender (OR = 1.95, 95%CI = 1.16–3.27), BMI (OR = 1.08, 95%CI = 1.02–1.14), overall comorbidity (OR = 1.07, 95%CI = 1.02–1.13) and depression (OR = 2.55, 95%CI = 1.33–4.88) were significant predictors of P-FoF. Conclusions T-FoF and P-FoF may be predicted by different sets of risk factors among older fallers. Thus, fallers should be screened for FoF especially when carrying specific risk factors, including female gender, osteoporosis, depression, living alone, impaired physical performance, BMI, comorbidity. These findings may be helpful in designing tailored intervention to blunt the risks related to consequence of FoF among older people experiencing falls. Trial registration The SCOPE study was registered prospectively at clinicaltrials.gov (NCT02691546; 25/02/2016).

En este texto examino, partiendo del Diario de Frida Kahlo, distintas líneas de lectura de la obra de la pintora mexicana para entenderla desde una perspectiva ecocrítica. Para esto trato de demostrar la presencia de un modo cómico en su obra que no solamente juega un papel importante en su ecología implícita, sino en su concepción de imagen y su relación con la palabra. Como punto de partida teórico recurrí al concepto de imagen en la poética de Octavio Paz y al de ecomímesis de Timothy Morton.

IntroductionWorldwide, COVID-19 pandemic lead to a large fall in the number of newly reported TB cases. In sub-Saharan Africa, microbiological diagnosis of TB is generally based on smear microscopy and Xpert MTB/RIF on sputum samples, but good quality sputum samples are often difficult to obtain, leading clinicians to rely on more invasive procedures for diagnosis. Aim of this study was to investigate pooled sensitivity and specificity of Xpert MTB/RIF on stool samples compared to respiratory microbiological reference standards in African countries.MethodsFour investigators independently searched PubMed, SCOPUS, and Web of Science until 12th October 2022, then screened titles and abstracts of all potentially eligible articles. The authors applied the eligibility criteria, considered the full texts. All the studies reported the data regarding true positive (TP), true negative (TN), false positive (FP) and false negative (FN). Risk of bias and applicability concerns were assessed with the Quadas-2 tool.Resultsoverall, among 130 papers initially screened, we evaluated 47 works, finally including 13 papers for a total of 2,352 participants, mainly children. The mean percentage of females was 49.6%, whilst the mean percentage of patients reporting HIV was 27.7%. Pooled sensitivity for Xpert MTB/RIF assay for detecting pulmonary tuberculosis was 68.2% (95%CI: 61.1–74.7%) even if characterized by a high heterogeneity (I2=53.7%). Specificity was almost 100% (99%, 95%CI: 97–100%; I2 = 45.7%). When divided for reference standard, in the six studies using sputum and nasogastric aspirate the accuracy was optimal (AUC = 0.99, SE = 0.02), whilst in the studies using only sputum for tuberculosis detection the AUC was 0.85 (with a SE = 0.16). The most common source of bias was exclusion of enrolled patients in the analysis.ConclusionsOur study confirms that, in Africa, stool Xpert MTB/RIF may be a useful rule-in test for children above and below 5 years of age under evaluation for pulmonary tuberculosis. Sensitivity increased substantially when using both sputum and nasogastric aspirate as reference samples.

INFN-CNAF is one of the Worldwide LHC Computing Grid (WLCG) Tier-1 data centres, providing computing, networking and storage resources to a wide variety of scientific collaborations, not limited to the four LHC (Large Hadron Collider) experiments. The INFN-CNAF data centre will move to a new location next year. At the same time, the requirements from our experiments and users are becoming increasingly challenging and new scientific communities have started or will soon start exploiting our resources. Currently, we are reengineering several services, in particular our monitoring infrastructure, in order to improve the day-by-day operations and to cope with the increasing complexity of the use cases and with the future expansion of the centre. This scenario led us to implement a data streaming infrastructure designed to enable log analysis, anomaly detection, threat hunting, integrity monitoring and incident response. Such data streaming platform has been organised to manage different kinds of data coming from heterogeneous sources, to support multi-tenancy and to be scalable. Moreover, we will be able to provide an on demand end-to-end data streaming application to those users/communities requesting such kind of facility. The infrastructure is based on the Apache Kafka platform, which provides streaming of events at large scale, with authorization and authentication configured at the topic level for ensuring data isolation and protection. Data can be consumed by different applications, such as those devoted to log analysis, which provide the capability to index large amounts of data and implement appropriate access policies to inspect and visualise information. In this contribution we will present and motivate our technological choices for the definition of the infrastructure, we will describe its components and we will depict use cases which can be addressed with this platform.

The Italian WLCG Tier-1 located in Bologna and managed by INFN-CNAF has a long tradition in supporting several research communities in the fields of High-Energy Physics, Astroparticle Physics, Gravitational Waves, Nuclear Physics and others, to which provides computing resources in the form of batch computing, both HPC, HTC and Cloud, and storage. Although the LHC experiments at CERN represent the main users of the Tier-1 resources, an increasing number of communities and experiments are also being supported in all of their computing activities. Due to this demanding user base, an efficient support system is needed in order to assure a smooth and appropriate exploitation of the computing infrastructure. In this framework, such a role is played by the Tier-1 User Support group, which acts as the entry point for services, support requests, and problem reports. The group makes use of multiple systems to meet the different needs and specificities of the supported experiments. Moreover, the group continuously maintains detailed knowledge base in the form of an on-line user guide and develops tools to advertise specific information about the services available to the communities in a form that is easy to access and use. The communication channels are represented by ticketing systems and also by mailing lists used for a more direct communication, allowing to promptly notify maintenance interventions, downtimes and more in general all the new features and services provided by the center. In this paper, the ticketing systems, tools, platforms and services that User Support offers, and the internal organization of the department will be described. Future workflow plans in view of the DATACLOUD project, which will require an increasing effort, will also be presented.

Having a long tradition in state-of-the-art distributed IT technologies, in the last couple of years INFN made available to its users “INFN Cloud”: a cloud infrastructure and related services portfolio dedicated to the scientific communities supported by INFN. Given the distributed nature of the infrastructure as well as the considerable number of technical solutions provided to the INFN users, it is important to have a reliable user support service aimed to properly interact both with INFN Cloud users and administrators. As an added value, proper training activities have been defined and differentiated to different types of users and the training courses are integrated with a rich set of user guides and technical documentation. In this article, an overview of the INFN Cloud, its evolution to DataCloud project, and the support and training activities will be provided and presented.

GvHD still remains, despite the continuous improvement of transplantation platforms, a fearful complication of transplantation from allogeneic donors. Being able to separate GvHD from GvL represents the greatest challenge in the allogeneic transplant setting. This may be possible through continuous improvement of cell therapy techniques. In this review, current cell therapies are taken into consideration, which are based on the use of TCR alpha/beta depletion, CD45RA depletion, T regulatory cell enrichment, NK-cell-based immunotherapies, and suicide gene therapies in order to prevent GvHD and maximally amplify the GvL effect in the setting of haploidentical transplantation.