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Background: Little is known about vulnerability to severe COVID-19 illness after vaccination completion with three doses of vaccine against COVID-19. Objectives: To identify individual features associated with increased risk of severe clinical manifestation of SARS-CoV-2 infections after receiving the third dose of vaccine against COVID-19. Methods: We performed a nested case-control study based on 3,360,116 citizens from Lombardy, Italy, aged 12 years or older who received the third dose of vaccine against COVID-19 from 20 September through 31 December 2021. Individuals were followed from 14 days after vaccination completion until the occurrence of severe COVID-19 illness, death unrelated to COVID-19, emigration or 15 March 2022. For each case, controls were randomly selected to be 1:10 matched for the date of vaccination completion and municipality of residence. The association between candidate predictors and outcome was assessed through multivariable conditional logistic regression models. Results: During 12,538,330 person-months of follow-up, 5171 cases of severe illness occurred. As age increased, a trend towards increasing odds of severe illness was observed. Male gender was a significant risk factor. As the number of contacts with the Regional Health Service increased, a trend towards increasing odds of severe illness was observed. Having had a previous SARS-CoV-2 infection was a significant protective factor. Having received the Moderna vaccine significantly decreased the odds of severe illness. Significant higher odds were associated with 42 diseases/conditions. Odds ratios ranged from 1.23 (diseases of the musculoskeletal system) to 5.00 (autoimmune disease). Conclusions: This study provides useful insights for establishing priority in fourth-dose vaccination programs.

Background: Scarce information is available on the duration of the protective effect of COVID-19 vaccination against the risk of SARS-CoV-2 infection and its severe clinical consequences. We investigated the effect of time since vaccine completion on the SARS-CoV-2 infection and its severe forms. Methods: In this retrospective observational analysis using the vaccination campaign integrated platform of the Italian region of Lombardy, 5 351 085 individuals aged 12 years or older who received complete vaccination from Jan 17 to July 31, 2021, were followed up from 14 days after vaccine completion until Oct 20, 2021. Changes over time in outcome rates (ie, SARS-CoV-2 infection and severe illness among vaccinated individuals) were analysed with age-period-cohort models. Trends in vaccine effectiveness (ie, outcomes comparison in vaccinated and unvaccinated individuals) were also measured. Findings: Overall, 14 140 infections and 2450 severe illnesses were documented, corresponding to incidence rates of 6·7 (95% CI 6·6–6·8) and 1·2 (1·1–1·2) cases per 10 000 person-months, respectively. From the first to the ninth month since vaccine completion, rates increased from 4·6 to 10·2 infections, and from 1·0 to 1·7 severe illnesses every 10 000 person-months. These figures correspond to relative reduction of vaccine effectiveness of 54·9% (95% CI 48·3–60·6) for infection and of 40·0% (16·2–57·0) for severe illness. The increasing infection rate was greater for individuals aged 60 years or older who received adenovirus-vectored vaccines (from 4·0 to 23·5 cases every 10 000 person-months). The increasing severe illness rates were similar for individuals receiving mRNA-based vaccines (from 1·1 to 1·5 every 10 000 person-months) and adenovirus-vectored vaccines (from 0·5 to 0·9 every 10 000 person-months). Interpretation: Although the risk of infection after vaccination, and even more of severe illness, remains low, the gradual increase in clinical outcomes related to SARS-CoV-2 infection suggests that the booster campaign should be accelerated and that social and individual protection measures against COVID-19 spread should not be abandoned. Funding: None.

INTRODUCTION/BACKGROUND: The USPSTF (United States Preventive Service Task Force) guidelines suggest criteria centering on smoking status and age to select patients for lung cancer screening. Despite the significant advances in screening with low-dose computed tomography (LDCT), cancer detection rate is low (1.1%), highlighting the need to investigate possible ways to refine the current lung cancer screening strategy. Our aim was to determine clinical risk factors predictive of lung cancer in an urban safety-net hospital. MATERIALS AND METHODS: We performed a retrospective chart review of 2847 patients who received LDCT screening for lung cancer between 3/1/2015 and 12/31/2019. Patient demographics and medical history were collected. A bivariate logistic regression was used to evaluate predictors of lung cancer. RESULTS: Compared to the National Lung Cancer Screening Trial (NLST) population, our screening cohort had significantly more African Americans (38.2% vs 4.5%, p

Background: Dendritic cell vaccination (DCV) strategies, thanks to a complex immune response, may flare tumor regression and improve patients’ long-term survival. This meta-analysis aims to assess the efficacy of DCV for newly diagnosed glioblastoma patients in clinical trials. Methods: The study databases, including PubMed, Web of Knowledge, Google Scholar, Scopus, and Cochrane, were searched by two blinded investigators considering eligible studies based on the following keywords: “glioblastoma multiforme”, “dendritic cell”, “vaccination”, “immunotherapy”, “immune system”, “immune response”, “chemotherapy”, “recurrence”, and “temozolomide”. Among the 157 screened, only 15 articles were eligible for the final analysis. Results: Regimens including DCV showed no effect on 6-month progression-free survival (PFS, HR = 1.385, 95% CI: 0.822–2.335, p = 0.673) or on 6-month overall survival (OS, HR = 1.408, 95% CI: 0.882–2.248, p = 0.754). In contrast, DCV led to significantly longer 1-year OS (HR = 1.936, 95% CI: 1.396–2.85, p = 0.001) and longer 2-year OS (HR = 3.670, 95% CI: 2.291–5.879, p = 0.001) versus control groups. Hence, introducing DCV could lead to increased 1 and 2-year survival of patients by 1.9 and 3.6 times, respectively. Conclusion: Antitumor regimens including DCV can effectively improve mid-term survival in patients suffering glioblastoma multiforme (GBM), but its impact emerges only after one year from vaccination. These data indicate the need for more time to achieve an anti-GBM immune response and suggest additional therapeutics, such as checkpoint inhibitors, to empower an earlier DCV action in patients affected by a very poor prognosis.

Viruses may evolve to increase the amount of encoded genetic information by means of overlapping genes, which utilize several reading frames. Such overlapping genes may be especially impactful for genomes of small size, often serving a source of novel accessory proteins, some of which play a crucial role in viral pathogenicity or in promoting the systemic spread of virus. Diverse genome-based metrics were proposed to facilitate recognition of overlapping genes that otherwise may be overlooked during genome annotation. They can detect the atypical codon bias associated with the overlap (e.g. a statistically significant reduction in variability at synonymous sites) or other sequence-composition features peculiar to overlapping genes. In this review, I compare nine computational methods, discuss their strengths and limitations, and survey how they were applied to detect candidate overlapping genes in the genome of SARS-CoV-2, the etiological agent of COVID-19 pandemic.

Acute-on-chronic liver failure (ACLF) is characterized predominantly by non-apoptotic forms of hepatocyte cell death. Necroptosis is a form of programmed lytic cell death in which receptor interacting protein kinase (RIPK) 1, RIPK3 and phosphorylated mixed lineage kinase domain-like (pMLKL) are key components. This study was performed to determine the role of RIPK1 mediated cell death in ACLF. RIPK3 plasma levels and hepatic expression of RIPK1, RIPK3, and pMLKL were measured in healthy volunteers, stable patients with cirrhosis, and in hospitalized cirrhotic patients with acutely decompensated cirrhosis, with and without ACLF (AD). The role of necroptosis in ACLF was studied in two animal models of ACLF using inhibitors of RIPK1, necrostatin-1 (NEC-1) and SML2100 (RIPA56). Plasma RIPK3 levels predicted the risk of 28- and 90-day mortality (AUROC, 0.653 (95%CI 0.530–0.776), 0.696 (95%CI 0.593–0.799)] and also the progression of patients from no ACLF to ACLF [0.744 (95%CI 0.593–0.895)] and the results were validated in a 2nd patient cohort. This pattern was replicated in a rodent model of ACLF that was induced by administration of lipopolysaccharide (LPS) to bile-duct ligated rats and carbon tetrachloride-induced fibrosis mice administered galactosamine (CCL4/GalN). Suppression of caspase-8 activity in ACLF rodent model was observed suggesting a switch from caspase-dependent cell death to necroptosis. NEC-1 treatment prior to administration of LPS significantly reduced the severity of ACLF manifested by reduced liver, kidney, and brain injury mirrored by reduced hepatic and renal cell death. Similar hepato-protective effects were observed with RIPA56 in a murine model of ACLF induced by CCL4/GalN. These data demonstrate for the first time the importance of RIPK1 mediated cell death in human and rodent ACLF. Inhibition of RIPK1 is a potential novel therapeutic approach to prevent progression of susceptible patients from no ACLF to ACLF.

In randomized clinical trials, the androgen-receptor inhibitor enzalutamide has demonstrated efficacy and safety in metastatic castration-resistant prostate cancer (mCRPC). This study captured efficacy, safety and patient-reported outcomes (PROs) of enzalutamide in mCRPC patients in a real-world European setting. PREMISE (NCT0249574) was a European, long-term, prospective, observational study in mCRPC patients prescribed enzalutamide as part of standard clinical practice. Patients were categorized based on prior docetaxel and/or abiraterone use. The primary endpoint was time to treatment failure (TTF), defined as time from enzalutamide initiation to permanent treatment discontinuation for any reason. Secondary endpoints included prostate-specific antigen (PSA) response, time to PSA progression, time to disease progression and safety. PROs included EuroQol 5-Dimension, 5-Level questionnaire, Functional Assessment of Cancer Therapy-Prostate and Brief Pain Inventory-Short Form. Overall, 1732 men were enrolled. Median TTF with enzalutamide was 12.9 months in the chemotherapy- and abiraterone-naïve cohort (Cohort 1) and 8.4 months in the postchemotherapy and abiraterone-naïve cohort (Cohort 2). Clinical outcomes based on secondary endpoints also varied between cohorts. Cohorts 1 and 2 showed small improvements in health-related quality of life and pain status. The proportions of patients reporting treatment-emergent adverse events (TEAEs) were 51.0% and 62.2% in Cohorts 1 and 2, respectively; enzalutamide-related TEAEs were similar in both cohorts. The most frequent TEAE across cohorts was fatigue. These data from unselected mCRPC patients in European, real-world, clinical-practice settings confirmed the benefits of enzalutamide previously shown in clinical trial outcomes, with safety results consistent with enzalutamide's known safety profile. ispartof: INTERNATIONAL JOURNAL OF CANCER vol:150 issue:5 pages:837-846 ispartof: location:United States status: published

Abstract Background The evolution of SARS-CoV-2 has led to the emergence of several new variants, and few data are available on the impact of vaccination on SARS-CoV-2 variants. We aimed to assess the association between natural (previous infection) and induced (partial or complete vaccination) exposure to SARS-CoV-2 and the onset of new infection supported by the delta variant, and of comparing it with that supported by alpha. Methods We performed a test-negative case-control study, by linking population-based registries of confirmed diagnoses of infection with SARS-CoV-2, vaccinations against Covid-19 and healthcare utilization databases of the Italian Lombardy Region. Four hundred ninety-six persons who between 27 December 2020 and 16 July 2021 had an infection by the delta variant were 1:1 matched with citizens affected by alphavariant and 1:10 matched with persons who had a negative molecular test, according to gender, age and date of molecular ascertainment. We used a conditional logistic regression for estimating relative risk reduction of either variants associated with natural and/or induced immunization and corresponding 95% confidence interval (CI). Results Previous infection was associated with 91% (95% CI 85% to 95%) reduced relative risk of reinfection, without evidence of significant differences between delta and alpha cases (p=0.547). Significant lower vaccinal protection against delta than alpha variant infection was observed with reduced relative risk associated with partial vaccination respectively of 29% (7% to 45%), and 62% (48% to 71%) (p=0.001), and with complete vaccination respectively of 75% (66% to 82%) and 90% (85% to 94%) (p=0.003). Conclusions Lower protection towards infections caused by the delta variant with respect to alpha variant was noticed, even after the completion of the vaccination cycle. This finding would support efforts to maximize both vaccine uptake with two doses and fulfilment with individual protection measures, especially as the delta variant is rampant worldwide presently.

Internal carotid artery (ICA) injuries during endoscopic endonasal surgery (EES) are rare life-threatening events. We describe a technique to manage ICA injuries based on the use of Foley catheters.A 26-year-old female underwent endoscopic transnasal trans-sphenoidal removal of pituitary adenoma. Cerebrospinal fluid leak occurred 4 days postoperatively. During repair procedure, accidental injury of ICA occurred. Emergency nasal packing through positioning of four Foley urologic catheters was successfully performed to stop bleeding. The patient did not report neurologic deficits.In author’s opinion, Foley catheters are suitable to obtain immediate bleeding control since they are rapidly available and easily usable.

The clinical spectrum of small fiber neuropathy (SFN) encompasses manifestations related to the involvement of thinly myelinated A-delta and unmyelinated C fibers, including not only the classical distal phenotype, but also a non-length-dependent (NLD) presentation that can be patchy, asymmetrical, upper limb-predominant, or diffuse. This narrative review is focused on NLD-SFN. The diagnosis of NLD-SFN can be problematic, due to its varied and often atypical presentation, and diagnostic criteria developed for distal SFN are not suitable for NLD-SFN. The topographic pattern of NLD-SFN is likely related to ganglionopathy restricted to the small neurons of dorsal root ganglia. It is often associated with systemic diseases, but about half the time is idiopathic. In comparison with distal SFN, immune-mediated diseases are more common than dysmetabolic conditions. Treatment is usually based on the management of neuropathic pain. Disease-modifying therapy, including immunotherapy, may be effective in patients with identified causes. Future research on NLD-SFN is expected to further clarify the interconnected aspects of phenotypic characterization, diagnostic criteria, and pathophysiology.

Although postharvest coffee fruit fermentation can improve coffee flavour and quality, the mycotoxin ochratoxin A (OTA) can also be a result of microbiological activity, albeit in the later drying step of coffee processing. To evaluate the possible occurrence of OTA contamination in postharvest fruit fermentation, fourteen coffees that entailed two different postharvest fruit fermentation times were evaluated. These coffees originated in the surroundings of the village of Pedra Menina in the qualified Denomination of Origin and coffee producer region of Caparao on the border between Minas Gerais and Espirito Santo states in Brazil. All coffees were classified according to the Specialty Coffee Association (SCA) protocol and 12 achieved specialty level. OTA was determined in all 14 coffees using immunoaffinity for sample clean-up and high-performance liquid chromatography with fluorescence detection for quantification. One sample presented an OTA concentration of 0.75 µg kg-1 and two samples showed OTA concentrations of 0.87 µg kg-1. The other samples had concentrations of OTA below the limit of quantification obtained in this work (0.64 µg kg-1). Thus, all samples showed OTA concentrations far below the most stringent maximum residue limit (MRL) of 5 µg kg-1 established for roasted coffees by European legislation. These low levels were similar to most of the previous results for Brazilian coffees listed and tabled in this work. This comparison showed that OTA contamination due to this kind of postharvest process - fruit fermentation - should not be a concern for producers and consumers of these fermented coffees.

No robust evidence is provided by literature regarding the management of intracranial hypertension following severe traumatic brain injury (TBI). This is mostly due to the lack of prospective randomized controlled trials (RCTs), the presence of studies containing extreme heterogeneously collected populations and controversial considerations about chosen outcome. A scientific society should provide guidelines for care management and scientific support for those areas for which evidence-based medicine has not been identified. However, RCTs in severe TBI have failed to establish intervention effectiveness, arising the need to make greater use of tools such as Consensus Conferences between experts, which have the advantage of providing recommendations based on experience, on the analysis of updated literature data and on the direct comparison of different logistic realities. The Italian scientific societies should provide guidelines following the national laws ruling the best medical practice. However, many limitations do not allow the collection of data supporting high levels of evidence for intracranial pressure (ICP) monitoring and decompressive craniectomy (DC) in patients with severe TBI. This intersociety document proposes best practice guidelines for this subsetting of patients to be adopted on a national Italian level, along with joint statements from "TBI Section" of the Italian Society of Neurosurgery (SINch) endorsed by the Neuroanesthesia and Neurocritical Care Study Group of the Italian Society of Anesthesia, Analgesia, Resuscitation and Intensive Care (SIAARTI). Presented here is a recap of recommendations on management of ICP and DC supported a high level of available evidence and rate of agreement expressed by the assemblies during the more recent consensus conferences, where members of both groups have had a role of active participants and supporters. The listed recommendations have been sent to a panel of experts consisting of the 107 members of the "TBI Section" of the SINch and the 111 members of the Neuroanesthesia and Neurocritical Care Study Group of the SIAARTI. The aim of the survey was to test a preliminary evaluation of the grade of predictable future adherence of the recommendations following this intersociety proposal. The following recommendations are suggested as representing best clinical practice, nevertheless, adoption of local multidisciplinary protocols regarding thresholds of ICP values, drug therapies, hemostasis management and perioperative care of decompressed patients is strongly recommended to improve treatment efficiency, to increase the quality of data collection and to provide more powerful evidence with future studies. Thus, for this future perspective a rapid overview of the role of the multimodal neuromonitoring in the optimal severe TBI management is also provided in this document. It is reasonable to assume that the recommendations reported in this paper will in future be updated by new observations arising from future trials. They are not binding, and this document should be offered as a guidance for clinical practice through an intersociety agreement, taking in consideration the low level of evidence.

«Progetto di Vita» ("PdV" Life Project) represents the crucial element to design and build the Quality of Life of persons with disabilities, in coherence with the UN Convention on the Rights of Persons with Disabilities. In Italy, Law no. 112/16 identifies in the PdV the principle around which to build a convergence of intents and interests for the realisation of the «Dopo di Noi» (After Us) that can take place «durante Noi» (during Us) through the construction of empowerment paths towards autonomy in a perspective of prevention, gradualness, emancipation and accompaniment to detachment. In order to experience autonomy «durante Noi», preparing for the «Dopo di Noi», the living space, the surrounding environment and the community of reference represent fundamental functional and/or spatial environments. The aim of this article is to map and analyse the good practices that have emerged from the concrete application of the Law through the activation of housing welfare projects that represent innovative forms of living built around the PdV approach.

Background Chordomas are rare primary tumors of the bone that arise from embryonic notochord. They are locally aggressive tumors with a high tendency for postsurgical recurrence. On the other hand, distant metastases are rare. When they occur, they involve lungs, liver, lymph nodes, and bones. Skin and subcutaneous tissue involvement is even rarer and usually occurs by direct extension of the primary tumor or by local recurrence. Distant cutaneous metastasis from chordoma is an exceptional finding, with fewer than 20 cases reported in the literature. All the cutaneous metastases described derive from sacral chordomas, except for 2 cases in which the source of metastasis is skull-base chordomas. Case Description We report the case of a 55-year-old man with skin metastasis from a cervical chordoma. Conclusions Metastasis has to be taken into account in the differential diagnosis when a new skin lesion appears in a patient with a past medical history of chordoma. To the best of our knowledge, this is the first case of cutaneous metastasis from spinal cervical chordoma. A systematic literature review was performed.

Rapporti anatomici e radiologici delle strutture cervicali in relazione al rachide: implicazioni per gli approcci cervicotomici anteriori al rachide.La posizione del framework faringolaringeo è importante nel decidere quale approccio al rachide cervicale adottare. L’obiettivo dello studio è di analizzare la posizione dell’osso ioide e della cartilagine cricoide in relazione ai livelli del rachide cervicale e discuterne le possibili implicazioni per gli accessi cervicotomici al rachide cervicale ed allo spazio prevertebrale. Infatti, per ridurre al minimo le complicanze legate a tale chirurgia ed incrementare l’efficacia del trattamento, la posizione ed estensione del processo patologico a carico del rachide dovrebbe essere inquadrata rispetto ai rapporti anatomici con l’asse faringo-laringeo del singolo paziente. È stata condotta un’analisi retrospettiva di 100 risonanze magnetiche cervicali, escludendo i pazienti che presentavano lesioni che potessero alterare i rapporti anatomici con le vertebre cervicali. Prendendo in esame le scansioni sagittali sulla linea mediana, l’osso ioide ed il margine inferiore della cricoide sono stati proiettati perpendicolarmente sulla superficie anteriore del rachide ed è stata misurata la distanza di queste dal punto di proiezione sulla colonna vertebrale. La distribuzione delle proiezioni dell’osso ioide si attestava tra gli spazi intervertebrali C2-C3 and C4-C5, mentre quella della cartilagine cricoide tra C4-C5 e C7-T1. La distanza media tra queste due strutture era di 49,1 ± 7,7 mm e vi era differenza statisticamente significativa tra sesso maschile e femminile. La posizione della cricoide influenzava significativamente la lunghezza dell’asse faringo-laringeo, mentre la posizione dell’osso ioide era spesso costante. Da quanto osservato, si evince che esista un ampio raggio di variabilità nella posizione dell’osso ioide e della cartilagine cricoidea rispetto ai livelli delle vertebre cervicali. Da ciò ne deriva che una associazione a priori tra specifici livelli cervicali e strutture del collo a rischio sarebbe poco accurata. L’utilizzo dei reperi proposti, facilmente identificabili radiologicamente, può guidare la scelta tra i diversi approcci cervicotomici anteriori al rachide cervicale, riducendo il rischio di complicanze chirurgiche.The position of the pharyngolaryngeal framework is very important in choosing the best surgical approach for cervical spine disease. The aim of the present paper is to investigate the position of the hyoid bone and cricoid cartilage in relation to the cervical spine. Moreover, the surgical implications for anterior transcervical approaches to the upper spine and the prevertebral space are discussed. To minimise complication rates and increase surgical effectiveness, the location and extent of the cervical spine disease should be evaluated in the context of the patient’s specific anatomy. A retrospective analysis of 100 cervical spine MRIs was conducted. Patients with diseases that could alter anatomic relationships of cervical structures were excluded. The mid-sagittal view of the hyoid and the inferior margin of the cricoid cartilage were projected perpendicularly to the anterior surface of the cervical vertebrae. The distance between these two landmarks was measured on the same view. The distribution of hyoid projections ranged between C2-C3 and C4-C5 intervertebral space, while the cricoid cartilage ranged between C4-C5 and C7-T1 intervertebral spaces. The mean distance between these two landmarks was 49.1 ± 7.7 mm, with statistically significant differences between males and females. The position of the cricoid cartilage significantly influenced the length of the pharyngolaryngeal framework, while the position of hyoid did not. A wide range of variability in the position of the hyoid bone and the cricoid cartilage in relation to cervical levels exists. This implies that an

Introduction We aimed to assess harms (post-vaccine myocarditis and pericarditis) and benefits (preventing severe disease) of COVID-19 vaccination. Methods We conducted a population-based retrospective cohort study. Using the integrated platform of the vaccination campaign of Lombardy Region (Italy), after the exclusion of 24,188 individuals not beneficiaries of the Regional Health Service, 9,184,146 citizens candidates to vaccine at December 27, 2020 were followed until November 30, 2021 (the loss to follow-up rate was 0.5%). From the date of administration of each vaccine dose to day 28 post-administration, three periods that covered exposure to the first, second, and third dose were defined. The benefit–risk profile of vaccines was performed by comparing the number needed to harm (NNH) and number needed to treat (NNT) by sex, age, and vaccine type. Results Incidence rates of myocarditis were 9.9 and 5.2 per million person-months during the exposure and no-exposure periods, respectively, and the incidence rates of pericarditis were 19.5 and 15.9 per million person-months, respectively. The risk of myocarditis was highest following exposure to the second dose of the Moderna vaccine (adjusted HR: 5.5, 95% CI: 3.7 to 8.1). Exposure to the Moderna vaccine was also associated with an increased risk of pericarditis (adjusted HR 2.2, 1.5 to 3.1). NNT was higher than NNH (9471 vs. 7213) for 16 to 19-year-old men who received the Moderna vaccine, while all other sex, age, and vaccine subgroups had a favourable harm-benefit profile. Conclusions Men 16 to 19 years of age has the highest rates of myocarditis within a few days after receiving the Moderna vaccines. The balance between harms and benefits was almost always in favour of vaccination.

Background: Using the knowledge gained during the first eleven months of the vaccine campaign in Lombardy, Italy, we provide an overview of the benefits of using reliable, complete, and rapidly available observational data to monitor the progress of the vaccine strategy. Methods: A population-based platform was implemented by linking four registries reporting individual data on: (i) date, type, and dose of vaccine dispensed; (ii) SARS-CoV-2 infections and hospital admissions and deaths due to COVID-19; (iii) inpatient diagnoses and outpatient services supplied by the Regional Health Services (RHS); and the (iv) health registry reporting and updating data on patient status. Background, methods, findings, and implications of eight COVID-19 relevant questions are reported. Results: Before starting the vaccine campaign, we identified high-risk individuals who need to be prioritized. During the vaccine campaign, we: (i) monitored the trend in the speed of the vaccine campaign progression and the number of prevented clinical outcomes; (ii) verified that available vaccines work in real-life, assessed their effectiveness-harm profile, and measured their reduced effectiveness against the delta variant. Finally, we studied the reduced effectiveness of the vaccine over time and identified risk factors of post-vaccine infection and severe illness. Conclusions: The correct use of rapidly available observational data of good quality and completeness generates reliable evidence to promptly inform patients and policymakers.

Amyotrophic lateral sclerosis (ALS) is known to represent a collection of overlapping syndromes. Various classification systems based on empirical observations have been proposed, but it is unclear to what extent they reflect ALS population substructures. We aimed to use machine-learning techniques to identify the number and nature of ALS subtypes to obtain a better understanding of this heterogeneity, enhance our understanding of the disease, and improve clinical care.In this retrospective study, we applied unsupervised Uniform Manifold Approximation and Projection [UMAP]) modelling, semi-supervised (neural network UMAP) modelling, and supervised (ensemble learning based on LightGBM) modelling to a population-based discovery cohort of patients who were diagnosed with ALS while living in the Piedmont and Valle d'Aosta regions of Italy, for whom detailed clinical data, such as age at symptom onset, were available. We excluded patients with missing Revised ALS Functional Rating Scale (ALSFRS-R) feature values from the unsupervised and semi-supervised steps. We replicated our findings in an independent population-based cohort of patients who were diagnosed with ALS while living in the Emilia Romagna region of Italy.Between Jan 1, 1995, and Dec 31, 2015, 2858 patients were entered in the discovery cohort. After excluding 497 (17%) patients with missing ALSFRS-R feature values, data for 42 clinical features across 2361 (83%) patients were available for the unsupervised and semi-supervised analysis. We found that semi-supervised machine learning produced the optimum clustering of the patients with ALS. These clusters roughly corresponded to the six clinical subtypes defined by the Chiò classification system (ie, bulbar, respiratory, flail arm, classical, pyramidal, and flail leg ALS). Between Jan 1, 2009, and March 1, 2018, 1097 patients were entered in the replication cohort. After excluding 108 (10%) patients with missing ALSFRS-R feature values, data for 42 clinical features across 989 patients were available for the unsupervised and semi-supervised analysis. All 1097 patients were included in the supervised analysis. The same clusters were identified in the replication cohort. By contrast, other ALS classification schemes, such as the El Escorial categories, Milano-Torino clinical staging, and King's clinical stages, did not adequately label the clusters. Supervised learning identified 11 clinical parameters that predicted ALS clinical subtypes with high accuracy (area under the curve 0·982 [95% CI 0·980-0·983]).Our data-driven study provides insight into the ALS population substructure and confirms that the Chiò classification system successfully identifies ALS subtypes. Additional validation is required to determine the accuracy and clinical use of these algorithms in assigning clinical subtypes. Nevertheless, our algorithms offer a broad insight into the clinical heterogeneity of ALS and help to determine the actual subtypes of disease that exist within this fatal neurodegenerative syndrome. The systematic identification of ALS subtypes will improve clinical care and clinical trial design.US National Institute on Aging, US National Institutes of Health, Italian Ministry of Health, European Commission, University of Torino Rita Levi Montalcini Department of Neurosciences, Emilia Romagna Regional Health Authority, and Italian Ministry of Education, University, and Research.For the Italian and German translations of the abstract see Supplementary Materials section.

A liquid chromatography tandem mass spectrometry method (LC-MS/MS) preceded by a rapid and simple QuEChERS-based sample preparation was developed and validated for the determination of acrylamide in non-centrifugal sugar (NCS), a solid product obtained from sugarcane juice without centrifugation, up to a concentration greater than 90 ºBrix. Adequate linearity in calibration curves, analytical selectivity and sensitivity were achieved. A limit of detection (LOD) and a limit of quantitation (LOQ) of 10 and 20 µg kg

Tetracyclines and polyether ionophores are veterinary drugs frequently used in animals reared for food production. Despite the benefits, residues can be harmful for human health if levels are higher than those considered safe. The aim of this study was to evaluate, by LC-MS/MS, tetracyclines residues in pasteurised milk samples marketed in São Paulo state, Brazil and estimate the exposure of the adult/adolescent/children population. Within the eight antibiotics monitored two were detected, tetracycline and 4-epitetracycline, found in 22.5% and 12.5% of the samples, respectively. Since the same samples had been previously tested for polyether ionophore residues, risk assessment based on dietary exposure to tetracyclines when considered individually and in combination with the ionophores was performed. The daily intakes were below the acceptable daily intake (ADI) for tetracycline. Considering the levels of monensin reported in a previous study, the combined exposure with tetracycline and 4-epi-tetracycline also indicated low potential health concerns.

Background: Previous studies on oxaliplatin and fluoropyrimidines as adjuvant therapy in older patients with stage III colon cancer (CC) produced conflicting results. Patients and methods: We assessed the impact of age on time to tumour recurrence (TTR), disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) in 2360 patients with stage III CC (1667 aged

The observables associated with protein intrinsic fluorescence - spectra, time decays, anisotropies - offer opportunities to monitor in real time and non-invasively a protein's functional form and its interchange with other forms with different functions. We employed these observables to sketch the fluorometric profiles of two functional forms of human thymidylate synthase (hTS), a homodimeric enzyme crucial for cell proliferation and thus targeted by anticancer drugs. The protein takes an active and an inactive form. Stabilization of the latter by peptides that, unlike classical hTS inhibitors, bind it at the monomer/monomer interface offers an alternative inhibition mechanism that promises to avoid the onset of drug resistance in anticancer therapy. The fluorescence features depicted herein can be used as tools to identify and quantify each of the two protein forms in solution, thus making it possible to investigate the kinetic and thermodynamic aspects of the active/inactive conformational interchange. Two examples of fluorometrically monitored interconversion kinetics are provided.

Objective Preoperative anemia is a risk factor for transfusions, morbidity and mortality in cardiac surgery. The aim of this study is to assess if an anemia intervention strategy before cardiac surgery is associated with reduced red blood cell (RBC) transfusion. Design Retrospective, propensity matched study Setting. University Clinical Research Hospital. Participants: two-hundred-twenty-eight adult cardiac surgery patients. Propensity matching was based on demographics, pre-treatment hemoglobin value, congestive heart failure, active endocarditis, serum creatinine, serum bilirubin, redo surgery, non-elective surgery, non-isolated surgery. Interventions Patients in the treated group received an anemia correction treatment at the pre-admission anesthesia clinic examination. The treatment included ferric carboxymaltose and/or erythropoietin based on the anemia diagnosis (absolute sideropenic; functional sideropenic; anemia of chronic disease). Treatment was single shot, at a median of 13 preoperative days (interquartile range 9-17 days. Patients in the control group were selected by propensity matching and did not receive any treatment. Measurements and Main Results Patients in the treated group received RBC transfusion in 61.4% of the cases vs. 76.3% in control group (odds ratio 0.49, 95% confidence interval 0.26-0.84, P=0.010) and a median units load of 1 unit (interquartile range 0-2) vs. 2 units (interquartile range 1-3) in control group (P=0.001). Patients in the treated group had significantly lower chest drain output, postoperative low cardiac output rate, and shorter intensive care and hospital stay. Conclusions Anemia correction before cardiac surgery is associated with a reduction in both the RBC transfusion rate and the amount of units transfused.

Patients with decompensated cirrhosis, particularly those with acute-on-chronic liver failure (ACLF), show profound alterations in plasma metabolomics. The aim of this study was to investigate the effect of treatment with simvastatin and rifaximin on plasma metabolites of patients with decompensated cirrhosis, specifically on compounds characteristic of the ACLF plasma metabolomic profile. Two cohorts of patients were investigated. The first was a descriptive cohort of patients with decompensated cirrhosis (n = 42), with and without ACLF. The second was an intervention cohort from the LIVERHOPE-SAFETY randomized, double-blind, placebo-controlled trial treated with simvastatin 20 mg/day plus rifaximin 1,200 mg/day (n = 12) or matching placebo (n = 13) for 3 months. Plasma samples were analyzed using ultrahigh performance liquid chromatography-tandem mass spectroscopy for plasma metabolomics characterization. ACLF was characterized by intense proteolysis and lipid alterations, specifically in pathways associated with inflammation and mitochondrial dysfunction, such as the tryptophan-kynurenine and carnitine beta-oxidation pathways. An ACLF-specific signature was identified. Treatment with simvastatin and rifaximin was associated with changes in 161 of 985 metabolites in comparison to treatment with placebo. A remarkable reduction in levels of metabolites from the tryptophan-kynurenine and carnitine pathways was found. Notably, 18 of the 32 metabolites of the ACLF signature were affected by the treatment. Conclusion: Treatment with simvastatin and rifaximin modulates some of the pathways that appear to be key in ACLF development. This study unveils some of the mechanisms involved in the effects of treatment with simvastatin and rifaximin in decompensated cirrhosis and sets the stage for the use of metabolomics to investigate new targeted therapies in cirrhosis to prevent ACLF development.

The desmoplastic nature of the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) prevents the infiltration of T cells and the penetration of chemotherapeutic drugs, posing a challenge to the validation of targeted therapies, including T cell immunotherapies. We present an in vitro 3D PDAC-TME model to observe and quantify T cell infiltration across the vasculature. In a three-channel microfluidic device, PDAC cells are cultured in a collagen matrix in the central channel surrounded, on one side, by endothelial cells (ECs) to mimic a blood vessel and, on the opposite side, by pancreatic stellate cells (PSCs) to simulate exocrine pancreas. The migration of T cells toward the tumor is quantified based on their activation state and TME composition. The presence of EC-lining drastically reduces T cell infiltration, confirming the essential role of the vasculature in controlling T cell trafficking. We show that activated T cells migrate ∼50% more than the not-activated ones toward the cancer cells. Correspondingly, in the absence of cancer cells, both activated and not-activated T cells present similar migration toward the PSCs. The proposed approach could help researchers in testing and optimizing immunotherapies for pancreatic cancer.

Deciphering how the human striatum develops is necessary for understanding the diseases that affect this region. To decode the transcriptional modules that regulate this structure during development, we compiled a catalog of 1116 long intergenic noncoding RNAs (lincRNAs) identified de novo and then profiled 96,789 single cells from the early human fetal striatum. We found that D1 and D2 medium spiny neurons (D1- and D2-MSNs) arise from a common progenitor and that lineage commitment is established during the postmitotic transition, across a pre-MSN phase that exhibits a continuous spectrum of fate determinants. We then uncovered cell type-specific gene regulatory networks that we validated through in silico perturbation. Finally, we identified human-specific lincRNAs that contribute to the phylogenetic divergence of this structure in humans. This work delineates the cellular hierarchies governing MSN lineage commitment.

ObjectiveTo retrospectively investigate safety and efficacy of nusinersen in a large cohort of adult Italian patients with spinal muscular atrophy (SMA).MethodsInclusion criteria were: (1) clinical and molecular diagnosis of SMA2 or SMA3; (2) nusinersen treatment started in adult age (>18 years); (3) clinical data available at least at baseline (T0-beginning of treatment) and 6 months (T6).ResultsWe included 116 patients (13 SMA2 and 103 SMA3) with median age at first administration of 34 years (range 18–72). The Hammersmith Functional Rating Scale Expanded (HFMSE) in patients with SMA3 increased significantly from baseline to T6 (median change +1 point, pConclusionsOur data provide further evidence of nusinersen safety and efficacy in adult SMA2 and SMA3, with the latter appearing to be cumulative over time. In patients with extremely advanced disease, effects on residual motor function are less clear.

Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF., info:eu-repo/semantics/published

Stereotactic gamma knife radiosurgery (GKS) may induce a transient enlargement of vestibular schwannomas (VS). This phenomenon, known as pseudoprogression or swelling, starts at about 3 months following GKS, peaks at about 6 months, and typically subsides thereafter, usually without significant neurological deterioration. We describe a 34-year-old female who developed an aggressive enlargement of a VS 1 month after GKS. The patient was treated with an immediate external ventricular drainage and surgical resection via retrosigmoid approach for an acute neurological deterioration due to hydrocephalus and brainstem compression. Histopathological examination revealed a VS with abundant intratumoral thrombosis and necrosis, suggesting that its rapid expansion could be related to massive radiation-induced tumor necrosis. The present case indicated that rapid life-threating enlargement of a VS may occur as an early complication following GKS.

Background Nickel is a ubiquitous element used in many everyday items. In recent decades nickel has become a leading allergen, which has become a public health problem. Objective To evaluate frequently used nickel products in Brazil. We investigated if these objects release nickel that is capable of inducing sensitization or cause clinical manifestations in terms of allergic contact dermatitis (ACD). Methods Dimethylglyoxime (DMG) spot tests assessed nickel release from several common utensils used in everyday life in Sao Paulo and Rio de Janeiro, Brazil. Results We tested 46 coins (two denominations) and 90 common utensils. Approximately 91.1% produced nickel-positive results using the DMG spot test. Conclusions The DMG limit of detection was 1.67 ppm of nickel. We observed that many objects in our test series released nickel above the DMG test limit. This observation suggests that nickel-sensitive individuals may be exposed to nickel, representing a public health issue.

With regards to health, chromium (Cr) is an ambiguous chemical element. Although it is considered to be an important micronutrient, it also is connected with several pathologies, including carcinogenicity. The mechanism of action of Cr and its compounds in humans is not yet fully understood. Currently, three possible mechanisms have been proposed for carcinogenesis: Cr(VI)-induced multistage carcinogenesis, genomic instability, and epigenetic modification. Therefore, in addition to the toxicity of this metal and its ions, human susceptibility to Cr-induced pathologies depends on external factors and individual characteristics, such as enzymatic polymorphisms, carriers, endogenous reducing system, adduct formation and stability, and efficiency of DNA repair mechanisms, among other factors. In fact, the variability of individual molecular constitutive factors, such as individual polymorphisms, creates an individualized environment for Cr toxicity. This mini-review contemplates the essential variables in this process.

Protection of the central nervous system (CNS) and cerebral homeostasis depend upon the blood-brain barrier (BBB) functions and permeability. BBB restrictive permeability hinders drug delivery for the treatment of several neurodegenerative diseases and brain tumors. Several in vivo animal models and in vitro systems have been developed to understand the BBB complex mechanisms and aid in the design of improved therapeutic strategies. However, there are still many limitations that should be addressed to achieve the structural and chemical environment of a human BBB. We developed a microfluidic-based model of the neurovascular unit. A monolayer of human cerebral endothelial cells (hCMEC-D3) was grown and cocultured with human brain microvascular pericytes (hBMVPC), and human induced pluripotent stem cells differentiated into astrocytes (hiPSC-AC) and neurons (hiPSC-N). To visualize the physiological morphology of each cell type, we used fluorescent cell-specific markers and confocal microscopy. Permeation of fluorescent solutes with different molecular weights was measured to demonstrate that the developed BBB was selectively permeable as a functional barrier.

Brain edema and/or acute hydrocephalus are common features that limit working space during early surgery of aneurysmal subarachnoid hemorrhage (aSAH). Intraoperative ventriculostomy offers an immediate brain relaxation. However, management and complications related to the routine use of intraoperative external ventricular drainage (iEVD) are not well investigated.We retrospectively reviewed all patients who were treated with pterional craniotomy and clipping for ruptured anterior circulation aneurysms in our center between 2012 and 2019. We included in this study all patients submitted to iEVD using the Paine's point on the side of craniotomy. Indication for positioning of an iEVD was given in all cases whenever initial cisternal dissection was hampered by the lack of cerebrospinal fluid (CSF) circulation due to SAH and/or hydrocephalus.In the study period, 162 patients with aSAH underwent surgical clipping. In 103 patients, an iEVD was used. The overall rate of iEVD-related complications was 6.7%, including 3 cases of catheter misplacement, one case of catheter obstruction, one case of related hemorrhage, and 2 cases of infection. The rate of shunt-dependent hydrocephalus was 16.5% (17/103 patients).In our experience, iEVD is a safe technique that facilitates dissection during early surgery for intracranial ruptured aneurysms, without requiring an additional burr hole procedure.

Background The impact of COVID-19 outbreak in the neurosurgical practice has been dramatic, imposing several limitations. The aim of this study is to present how the neurosurgical departments of Emilia-Romagna, a northern Italian region, have re-set their organization to maintain the higher standard of care as possible. Methods All OR and out-patients activities performed during the COVID-19 emergency in the neurosurgical department of Emilia-Romagna have been collected and compared to the means of the same timeframe in 2018 and 2019. Results In 2020, 205 surgical procedures and 466 out-patients consultations have been performed, representing respectively 28.8% and 26.4% of the previous biennium. The most of OR procedures had been emergencies/urgencies and oncological patients (respectively 113 and 66 vs 164.5 and 84.5 of the previous biennium), while elective surgeries decrease up to -97.1%, as for spinal nerves and endoscopic skull base procedures. The patients phone contacts and telemedicine evaluations of their examinations have permitted to reduce the hospital access for outpatients of 75.6%, but these modalities have, also, permitted to follow-up a large number of cases. Conclusions The outbreak of COVID-19 has imposed several limits to our current practice, however this should not represent an excuse to reduce the standard of care. In our experience, the net integration of different local centers has permitted for each of them to effectively cope the crisis, managing the local cases requiring a prompt surgery and keeping the care continuity with already discharged patients.

Background. The prognostic factors for surgically removed spinal hemangioblastomas, the impact of VHL disease on outcome, and the role of intraoperative neuromonitoring are still not completely clear. The aim of this study was to review our experience with spinal hemangioblastomas in order to assess potential predictors of neurological outcome after surgery.Methods. All cases of spinal hemangioblastomas removed at two Italian academic institutions from 1985 to 2020 were reviewed. Data about clinical presentation and symptoms duration, diagnosis of VHL, surgical approach, use of IONM, duration of hospital stay, follow up, McCormick grade before and after surgery were extracted.Results. Sixty-one patients (31 F, 30 M) underwent 69 surgeries to remove 74 spinal hemangioblastomas (37 cervical, 32 thoracic, 5 lumbar). Improvement was found in 32.3% of cases, neurological condition remained stable in 51.6% of cases, and deteriorated in 16.1% of patients.A worsening trend in VHL patients and an improvement trend in non-VHL patients were detected, despite the lack of statistical significance. Laminotomy and use of IONM were found to be associated with better outcome, although no association was found between surgery without IOM and worse outcome.Conclusion. In most cases, patients affected by spinal hemangioblastomas can expect a good long-term outcome. In our experience, laminotomy seems to be associated with better outcome compared to laminectomy. While its absence is not associated with worse outcome, IONM seems to be associated with a better neurological outcome. Our study suggests that the more impaired the preoperative neurological condition, the worse the outcome.

To date, there is no compilation of evidence-based information associating photobiomodulation effect and salivary glands. This systematic review aims to assess photobiomodulation effect of low intensity laser on salivary glands in the presence of systemic diseases. MEDLINE databases were searched in duplicate through December 2018. In vivo studies and clinical trials were included if photobiomodulation was performed in salivary glands of animal (rat or mice) or human in the presence of systemic disease. The methodological quality was assessed in duplicate using the modified Newcastle-Ottawa scale (NOS). Search strategy identified 483 potentially eligible articles, and 449 were included. The Boolean search naturally leads to a high amount of works the majority of which were excluded because the analysis of the title and abstract demonstrated it was not focusing on PBM. Only 34 studies were selected for the full-text analysis, of which 5 were excluded due to non-use of photobiomodulation, 4 due to lack of control group, 2 because they were studies of cell cultures and 1 because they did not have the total of animals used. Thus, 21 papers were included for the critical evaluation of the impact of photobiomodulation on the major salivary glands; the studies used rats (n = 10) and humans (n = 11). Although studies reported an increase in the salivary rate, decrease in pain, and increase in quality of life after the PBM, the lack of standards for the application of light and reporting of the parameters, make it hard to reproduce the results. This topic is still in need for further research.

The Lombardy region has been one of the areas most affected by the COVID-19 pandemic since the first months of 2020, providing real-life experiences in the acute phase. It is unclear how the respiratory rehabilitation network responded to this emergency. The aims of this retrospective study were: i) to analyze clinical, functional, and disability data at admission; ii) describe assessment tools and rehabilitative programs; iii) evaluate improvement after rehabilitation. The study was conducted on data collected from ten pulmonary rehabilitation centers in Lombardy, between the period of March 1st 2020 to March 1st 2021, in patients with respiratory failure recovering from COVID-19 both at admission and discharge. The study included demographics, comorbidities, nutritional status, risk of falls, disability status (Barthel index; Short Physical Performance Battery (SPPB); 6 minutes walking test (6MWT), symptoms (dyspnoea with Barthel Dyspnoea and MRC Dyspnoea Scale), length of stay, discharge destination, need for mechanical ventilation, respiratory function, assessment/outcomes indices, and prescribed rehabilitative programs. 413 patients were analyzed. Length of stay in acute and rehabilitative units was less than 30 days. Fifty % of patients used non-invasive ventilation during their stay. Functional status was mildly compromised for forced volumes and oxygenation, while severely compromised for diffusion capacity. Independency was low while physical performance status very low. At discharge, 318 (77%) patients were sent home, 83 (20.1%) were transferred to an acute unit and 12 (2.9%) passed away. Barthel Index and 6MWT were the most used, while MRC score was the least used outcome parameter. The 5 main rehabilitative activities were walking (90.8 %), transfer from bed to armchair (77.5%), limb mobilization in bed (76%), balance (71.2%), and cycle-ergometer or treadmill (43.1%). A huge difference was found in admission, discharge, and delta change among different rehabilitative centers. When available, all outcomes showed a significant improvement. With the limitation of a retrospective study with a clear amount of missing data, COVID-19 subjects admitted to rehabilitative centers presented a reduced physical performance, symptoms of dyspnoea, and severe disability. The 6MWT and Barthel index were the most used measurement.

Post-transplantation cyclophosphamide (PTCy) has emerged as a promising graft-versus-host-disease (GVHD) prophylaxis in the setting of allogeneic hematopoietic stem cell transplantation (HSCT) from haploidentical donors and more recently in matched donor transplants. Herein, we describe our real-life experience on 249 adult patients undergoing allogeneic HSCT, from HLA-matched related (MRD), HLA-matched unrelated (MUD), or mismatched related donors (MMRD). Patients received unmanipulated peripheral blood stem cells (PBSCs), using a GVHD prophylaxis with PTCy and sirolimus. Mycophenolate mofetil was added in MUD or MMRD. In the HLA-matched donor group (MRD, n = 48, MUD, n = 50), the cumulative incidence of grades II-IV and III-IV acute GvHD was 23% and 9% at 100 days, respectively. The cumulative incidence of chronic GvHD was 25% at 2 years, severe only for 5% of the patients. The cumulative incidences of relapse and transplant-related mortality (TRM) were 31% and 9% at 2 years, respectively. The 2-year overall survival (OS) was 72% and progression-free survival (PFS) 60%; the composite endpoint of GvHD/relapse-free survival (GRFS) was 52% at 2 years. In the haploidentical donor group (n = 151), we documented a cumulative incidence of grades II-IV and III-IV acute GVHD of 35% and 20% at 100 days, respectively, and a cumulative incidence of chronic GvHD of 39% at 2 years. We observed severe chronic GVHD in 15% of the patients. The cumulative incidence of relapse and TRM was 32% and 25% at 2 years, respectively. The 2-year OS was 48%, whereas PFS was 43%; GRFS was 28% at 2 years. However, more patients in the haploidentical group presented high/very high disease risk index (DRI) and higher HCT-comorbidity index. In patients classified in the low-intermediate DRI, 2-year GRFS was 53% in MRD, 65% in MUD, and 46% in haploidentical HSCT (P = .33). Sirolimus-PTCy platform deserves further investigation as an alternative to calcineurin-inhibitor–based GVHD prophylaxis for all donor sources. In patients presenting a low-intermediate DRI, this strategy translates in relevant survival independently from the transplant source.

Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF phenotype (AD-ACLF) defined by organ failure(s). Precipitants may induce AD. This multicenter, prospective, observational PREDICT study (NCT03056612) analyzes and characterizes the precipitants leading to both of these AD phenotypes., info:eu-repo/semantics/published

Simultaneous EEG-fMRI can contribute to identify the epileptogenic zone (EZ) in focal epilepsies. However, fMRI maps related to Interictal Epileptiform Discharges (IED) commonly show multiple regions of signal change rather than focal ones. Dynamic causal modeling (DCM) can estimate effective connectivity, i.e. the causal effects exerted by one brain region over another, based on fMRI data. Here, we employed DCM on fMRI data in 10 focal epilepsy patients with multiple IED-related regions of BOLD signal change, to test whether this approach can help the localization process of EZ. For each subject, a family of competing deterministic, plausible DCM models were constructed using IED as autonomous input at each node, one at time. The DCM findings were compared to the presurgical evaluation results and classified as: "Concordant" if the node identified by DCM matches the presumed focus, "Discordant" if the node is distant from the presumed focus, or "Inconclusive" (no statistically significant result). Furthermore, patients who subsequently underwent intracranial EEG recordings or surgery were considered as having an independent validation of DCM results. The effective connectivity focus identified using DCM was Concordant in 7 patients, Discordant in two cases and Inconclusive in one. In four of the 6 patients operated, the DCM findings were validated. Notably, the two Discordant and Invalidated results were found in patients with poor surgical outcome. Our findings provide preliminary evidence to support the applicability of DCM on fMRI data to investigate the epileptic networks in focal epilepsy and, particularly, to identify the EZ in complex cases.

Protection of the central nervous system (CNS) and cerebral homeostasis depend upon the blood-brain barrier (BBB) functions and permeability. BBB restrictive permeability hinders drug delivery for the treatment of several neurodegenerative diseases and brain tumors. Several in vivo animal models and in vitro systems have been developed to understand the BBB complex mechanisms and aid in the design of improved therapeutic strategies. However, there are still many limitations that should be addressed to achieve the structural and chemical environment of a human BBB. We developed a microfluidic-based model of the neurovascular unit. A monolayer of human cerebral endothelial cells (hCMEC-D3) was grown and cocultured with human brain microvascular pericytes (hBMVPC), and human induced pluripotent stem cells differentiated into astrocytes (hiPSC-AC) and neurons (hiPSC-N). To visualize the physiological morphology of each cell type, we used fluorescent cell-specific markers and confocal microscopy. Permeation of fluorescent solutes with different molecular weights was measured to demonstrate that the developed BBB was selectively permeable as a functional barrier.

Secondary acute myeloid leukemia (sAML) poorly responds to conventional treatments and allogeneic stem cell transplantation (HSCT). We evaluated toxicity and efficacy of CPX-351 in 71 elderly patients (median age 66 years) with sAML enrolled in the Italian Named (Compassionate) Use Program. Sixty days treatment-related mortality was 7% (5/71). The response rate at the end of treatment was: CR/CRi in 50/71 patients (70.4%), PR in 6/71 (8.5%), and NR in 10/71 (19.7%). After a median follow-up of 11 months relapse was observed in 10/50 patients (20%) and 12 months cumulative incidence of relapse (CIR) was 23.6%. Median duration of response was not reached. In competing risk analysis, CIR was reduced when HSCT was performed in first CR (12 months CIR of 5% and 37.4%, respectively, for patients receiving (=20) or not (=30) HSCT, p = 0.012). Twelve-months OS was 68.6% (median not reached). In landmark analysis, HSCT in CR1 was the only significant predictor of longer survival (12 months OS of 100 and 70.5%, for patients undergoing or not HSCT in CR1, respectively, p = 0.011). In conclusion, we extend to a real-life setting, the notion that CPX is an effective regimen for high risk AML patients and may improve the results of HSCT.

Objectives To evaluate ceftazidime/avibactam (C/A) and ceftolozane/tazobactam (C/T) use in haematological patients with febrile neutropenia receiving high-dose chemotherapy and haematopoietic stem cell transplantation (HSCT). Methods A retrospective study was conducted to assess C/A and C/T efficacy through infection-related mortality (IRM) and bacteraemia clearance for carbapenem-resistant Gram-negative bacteria (CR-GNB) pre-engraftment blood-stream infections (PE-BSIs) between January–December 2018. Results Seventy patients underwent allogeneic HSCT: C/A and C/T were dispensed in 13% and 3%, respectively. C/A was administered as definite therapy for carbapenem-resistant Klebsiella pneumoniae (CR-Kp) PE-BSI in four carriers (bacteraemia clearance in 5 days), empirical therapy for a clinically documented infection in two patients (one carrier with pneumonia and one non-carrier with shock) and empirical therapy for fever of unknown origin in three CR-Kp carriers. C/T was administered as definite therapy for carbapenem-resistant Pseudomonas aeruginosa (CR-Pa) intra-abdominal infection in one carrier and empirical therapy for a clinically documented infection (pneumonia) in one non-carrier. Among patients without PE-BSIs and with Gram-positive bacteria PE-BSIs, IRM was 0% at +30 days; conversely, it was 30% in GNB PE-BSIs (two CR-Kp and one CR-Pa C/T-resistant). Thirty-nine patients underwent autologous HSCT: C/A and C/T were administered, respectively, as definite therapy for CR-Kp PE-BSI in one carrier (bacteraemia clearance in 3 days) and for Pa PE-BSI (three strains, one CR-Pa) in one non-carrier (bacteraemia clearance in 2 days). Overall, IRM at +30 days was 0%. Conclusions Monitoring multidrug-resistant GNB colonisation enabled selection of carriers who benefit from prompt administration of new antibiotics, improving HSCT outcomes in a high-risk population. C/A and C/T were effective in bacteraemia clearance; unfortunately, multidrug-resistant GNB PE-BSIs were still a burden to IRM.

Magnetic resonance imaging (MRI) is the current gold standard for the diagnosis of brain tumors. However, despite the development of MRI techniques, the differential diagnosis of central nervous system (CNS) primary pathologies, such as lymphoma and glioblastoma or tumor-like brain lesions and glioma, is often challenging. MRI can be supported by in vivo magnetic resonance spectroscopy (MRS) to enhance its diagnostic power and multiproject-multicenter evaluations of classification of brain tumors have shown that an accuracy around 90% can be achieved for most of the pairwise discrimination problems. However, the survival rate for patients affected by gliomas is still low. The High-Resolution Magic-Angle-Spinning Nuclear Magnetic Resonance (HR-MAS NMR) metabolomics studies may be helpful for the discrimination of gliomas grades and the development of new strategies for clinical intervention. Here, we propose to use T2 -filtered, diffusion-filtered and conventional water-presaturated spectra to try to extract as much information as possible, fusing the data gathered by these different NMR experiments and applying a chemometric approach based on Multivariate Curve Resolution (MCR). Biomarkers important for glioma's discrimination were found. In particular, we focused our attention on cystathionine (Cyst) that shows promise as a biomarker for the better prognosis of glioma tumors.

SETBP1 variants occur as somatic mutations in several hematological malignancies such as atypical chronic myeloid leukemia and as de novo germline mutations in the Schinzel–Giedion syndrome. Here we show that SETBP1 binds to gDNA in AT-rich promoter regions, causing activation of gene expression through recruitment of a HCF1/KMT2A/PHF8 epigenetic complex. Deletion of two AT-hooks abrogates the binding of SETBP1 to gDNA and impairs target gene upregulation. Genes controlled by SETBP1 such as MECOM are significantly upregulated in leukemias containing SETBP1 mutations. Gene ontology analysis of deregulated SETBP1 target genes indicates that they are also key controllers of visceral organ development and brain morphogenesis. In line with these findings, in utero brain electroporation of mutated SETBP1 causes impairment of mouse neurogenesis with a profound delay in neuronal migration. In summary, this work unveils a SETBP1 function that directly affects gene transcription and clarifies the mechanism operating in myeloid malignancies and in the Schinzel–Giedion syndrome caused by SETBP1 mutations., SETBP1 variants occur as somatic mutations in several malignancies and as de novo germline mutations in developmental disorders. Here the authors provide evidence that SETBP1 binds to gDNA in AT-rich promoter regions to promote target gene upregulation, indicating SETBP1 functions directly to regulate transcription.

Sedentary behavior emerges as an important determinant of health in elderly persons, but its relationship to multimorbidity and its patterns in the Brazilian population have received little attention in epidemiological studies. Such associations can assist the elaboration of public policies aimed at modification of this behavior. This study thus aimed to assess the association between sedentary behavior and multimorbidity and its patterns in elderly Brazilians. This was a cross-sectional study of 43,554 elderly Brazilians in the Brazilian National Health Survey, 2019. Self-reported SB was categorized as3; 3-6; and6 hours a day. The presence of multimorbidity and its patterns were analyzed by self-report of two or more chronic diseases, where the three established patterns considered the diseases with similar clinical characteristics: (1) cardiopulmonary; (2) vascular-metabolic; and (3) mental-musculoskeletal. The associations were measured by binary logistic regression. Elderly persons that spent 3-6 hours/day in sedentary behavior had lower odds (OR = 1.39; 95%CI: 1.29; 1.50) of presenting multimorbidity, vascular-metabolic pattern (OR = 1.39; 95%CI: 1.29; 1.50), and mental-musculoskeletal pattern (OR = 1.11; 95%CI: 1.00; 1.24). Sedentary behavior6 hours/day was associated with higher odds of multimorbidity (OR = 1.58; 95%CI: 1.43; 1.74) and the cardiopulmonary (OR = 1.73; 95%CI: 1.33; 2.27), vascular-metabolic (OR = 1.49; 95%CI: 1.35; 1.64), and mental-musculoskeletal (OR = 1.15; 95%CI: 1.01; 1.31) patterns when compared to elders with 3 hours/day of sedentary behavior. This showed that extensive time in sedentary behavior is a relevant risk factor for multimorbidity and its patterns in the elderly.O comportamento sedentário emerge como um importante determinante da saúde da pessoa idosa, no entanto, sua relação com a multimorbidade e seus padrões de acometimento em estudos epidemiológicos têm sido pouco explorados na população brasileira. Tais associações poderão auxiliar na elaboração de políticas públicas visando à modificação desse comportamento. Assim, o objetivo deste estudo foi avaliar a associação entre comportamento sedentário com multimorbidade e seus padrões em idosos brasileiros. Estudo transversal, com 43.554 idosos da Pesquisa Nacional de Saúde de 2019. O comportamento sedentário autorreferido foi categorizado em3; 3-6; e6 horas por dia. A presença de multimorbidade e seus padrões foram analisados pelo autorrelato da coexistência de duas ou mais doenças crônicas, sendo que os três padrões estabelecidos consideraram as doenças com características clínicas similares: (1) cardiopulmonar; (2) vascular-metabólico; e (3) mental-musculoesquelético. As associações foram realizadas pela regressão logística binária. Os idosos que despendiam 3-6 horas/dia em comportamento sedentário tiveram maiores chances (OR = 1,39; IC95%: 1,29; 1,50) de apresentar multimorbidade, padrão vascular-metabólico (OR = 1,39; IC95%: 1,29; 1,50) e mental-musculoesquelético (OR = 1,11; IC95%: 1,00; 1,24). Quando o comportamento sedentário foi6 horas/dia, houve maiores chances de multimorbidade (OR = 1,58; IC95%: 1,43; 1,74) e dos padrões cardiopulmonar (OR = 1,73; IC95%: 1,33; 2,27), vascular-metabólico (OR = 1,49; IC95%: 1,35; 1,64) e mental-musculoesquelético (OR = 1,15; IC95%: 1,01; 1,31), quando comparados àqueles que ficavam até 3 horas/dia. Dessa forma, evidenciou-se que tempos elevados em comportamento sedentário são fatores de risco relevantes para a ocorrência de multimorbidade e seus padrões em idosos.El comportamiento sedentario emerge como un importante determinante de salud en personas ancianas, no obstante, su relación con la multimorbilidad y los patrones de enfrentamiento a la misma en estudios epidemiológicos se han investigado poco en la población brasileña. Tales asociaciones podrán apoyar en la elaboración de políticas públicas, con vistas a la modificación de ese comportamiento. Por ello, el objetivo de este estudio fue evaluar la asociación entre comportamiento sedentario con multimorbilidad y sus patrones en ancianos brasileños. Es un estudio transversal, con 43.554 ancianos de la Encuesta Nacional de Salud de 2019. El comportamiento sedentario autoinformado se categorizó en3; 3-6; y6 horas por día. La presencia de multimorbilidad y sus patrones se analizaron mediante el autoinforme de la coexistencia de dos o más enfermedades crónicas, siendo que los tres patrones establecidos consideraron las enfermedades con características clínicas similares: (1) cardiopulmonar; (2) vascular-metabólica y (3) mental-musculoesquelética. Las asociaciones fueron realizadas mediante regresión logística binaria. Los ancianos que pasaban 3-6h/día en comportamiento sedentario tuvieron mayores oportunidades (OR = 1,39; IC95%: 1,29; 1,50) de presentar multimorbilidad, patrón vascular-metabólico (OR = 1,39; IC95%: 1,29; 1,50) y mental-musculoesquelético (OR = 1,11; IC95%: 1,00; 1,24). Cuando el comportamiento sedentario fue6 horas/día hubo mayores oportunidades de multimorbilidad (OR = 1,58; IC95%: 1,43; 1,74), y de los patrones cardiopulmonar (OR = 1,73; IC95%: 1,33; 2,27), vascular-metabólico (OR = 1,49; IC95%: 1,35; 1,64) y mental-musculoesquelético (OR = 1,15; IC95%: 1,01; 1,31), cuando se compara con aquellos que estaban hasta 3 horas/día. De esa forma, se evidenció que tiempos elevados en comportamiento sedentario se mostraron factores de riesgo relevantes para la ocurrencia de multimorbilidad y sus patrones en ancianos.

Objective The objective of this study was to understand the effect of historical redlining (preclusion from home loans and wealth-building for Black Americans) and its downstream factors on the completion of lung cancer screening in Boston. Methods Patients within our institution were identified as eligible for lung cancer screening on the basis of the United State Preventive Service Task Force criteria and patient charts were reviewed to determine if patients completed low-dose computed tomography screening. Individual addresses were geocoded and overlayed with original 1930 Home Owner Loan Corporation redlining vector files. Structural equation models were used to estimate the odds of screening for Black and White patients, interacted with sex, in redlined and nonredlined areas. Results Black patients had a 44% lower odds of screening compared with White (odds ratio [OR], 0.66; 95% CI, 0.52-0.85). With race as a mediator, Black patients in redlined areas were 61% less likely to undergo screening than White patients (OR, 0.39; 95% CI, 0.24-0.64). Similarly, in redlined areas Black women had 61% (OR, 0.39; 95% CI, 0.21-0.73) and Black men 47% (OR, 0.53; 95% CI, 0.29-0.98) lower odds of screening compared with White men in redlined areas. Conclusions Despite higher rates of lung cancer screening in redlined areas, Black race mediated worse screening rates in these areas, suggesting racist structural factors contributing to the disparities in lung cancer screening completion among Black and White patients. Furthermore, these disparities were more apparent in Black women, suggesting that racial and gender intersectional discrimination are important in lung cancer screening completion.

Background During surgery in the posterior fossa in the prone position, blood can sometimes fill the surgical field, due both to the less efficient venous drainage compared to the sitting position and the horizontally positioned surgical field itself. In some cases, blood clots can wedge into the cerebral aqueduct and the third ventricle, and potentially cause acute hydrocephalus during the postoperative course. Objective To illustrate a technique that can be used in these cases: the use of a flexible scope introduced through the opened roof of the fourth ventricle with a freehand technique allows the navigation of the fourth ventricle, the cerebral aqueduct, and the third ventricle in order to explore the cerebrospinal fluid pathways and eventually aspirate blood clots and surgical debris. Methods We report on one patient affected by an ependymoma of the fourth ventricle, for whom we used a flexible neuroendoscope to explore and clear blood clots from the cerebral aqueduct and the third ventricle after the resection of the tumor in the prone position. Blood is aspirated with a syringe using the working channel of the scope as a sucker. Results A large blood clot that was lying on the roof of the third ventricle was aspirated, setting the ventricle completely free. Other clots were aspirated from the right foramen of Monro and from the optic recess. Conclusion We describe this novel technique, which represents a safe and efficient way to clear the surgical field at the end of posterior fossa surgery in the prone position. The unusual endoscopic visual perspective and instrument maneuvers are easily handled with proper neuroendoscopic training.

Tumor targeting by genetically modified mesenchymal stromal/stem cells (MSCs) carrying anti-cancer molecules represents a promising cell-based strategy. We previously showed that the pro-apoptotic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can be successfully delivered by MSCs to cancer sites. While the interaction between TRAIL and its receptors is clear, more obscure is the way in which MSCs can selectively target tumors and their antigens. Several neuroectoderm-derived neoplasms, including glioblastoma (GBM), sarcomas, and neuroblastoma, express high levels of the tumor-associated antigen GD2. We have already challenged this cell surface disialoganglioside by a chimeric antigen receptor (CAR)-T cell approach against neuroblastoma. With the intent to maximize the therapeutic profile of MSCs delivering TRAIL, we here originally developed a bi-functional strategy where TRAIL is delivered by MSCs that are also gene modified with the truncated form of the anti-GD2 CAR (GD2 tCAR) to mediate an immunoselective recognition of GD2-positive tumors. These bi-functional MSCs expressed high levels of TRAIL and GD2 tCAR associated with a robust anti-tumor activity against GD2-positive GBM cells. Most importantly, the anti-cancer action was reinforced by the enhanced targeting potential of such bi-functional cells. Collectively, our results suggest that a truncated anti-GD2 CAR might be a powerful new tool to redirect MSCs carrying TRAIL against GD2-expressing tumors. This affinity-based dual targeting holds the promise to combine site-specific and prolonged retention of MSCs in GD2-expressing tumors, thereby providing a more effective delivery of TRAIL for still incurable cancers.

RNA-Seq has become the de facto standard technique for characterization and quantification of transcriptomes, and a large number of methods and tools have been proposed to model and detect differential gene expression based on the comparison of transcript abundances across different samples. However, state-of-the-art methods for this task are usually designed for pairwise comparisons, that is, can identify significant variation of expression only between two conditions or samples. We describe the use of RNentropy, a methodology based on information theory, devised to overcome this limitation. RNentropy can thus detect significant variations of gene expression in RNA-Seq data across any number of samples and conditions, and can be applied downstream of any analysis pipeline for the quantification of gene expression from raw sequencing data. RNentropy takes as input gene (or transcript) expression values, defined with any measure suitable for the comparison of transcript levels across samples and conditions. The output consists of genes (or transcripts) exhibiting significant variation of expression across the conditions studied, together with the samples in which they result to be over- or underexpressed. RNentropy is implemented as an R package and freely available from the CRAN repository. We provide a detailed guide to the functions and parameters of the package and usage examples to demonstrate the software capabilities, also showing how it can be applied to the analysis of single-cell RNA sequencing data.