Trends in severe outcomes in SARS-CoV-2-positive hospitalized patients with rheumatic diseases: a monocentric observational and case-control study in northern Italy.

Rheumatic disease patients are at greater risk of infection due to their disease, comorbidities, and immunosuppressive therapy. COVID-19 outcomes in this patient setting appeared to be similar to those of the general population. However, data on this topic were mainly related to small studies on a limited number of patients. Consequently, to date, this field remains poorly explored, particularly in the pre-vaccine era. This monocentric study aimed to describe the intrahospital mortality in rheumatic patients with SARS-CoV-2 consecutively hospitalized from 21 February to 31 December 2020, before anti-SARS-CoV-2 vaccine administration spread, compared with non-rheumatic patients. Of 2491 included patients, 65 [3%, median (interquartile range) age 75 (64.76-82.239 years, 65% women] were suffering from rheumatic diseases. A total of 20 deaths were reported [case fatality rate 31%, 95% confidence interval (CI): 19-42] compared with 433 deaths (19%, 95% CI: 17-20) in patients without rheumatic diseases (p=0.024). However, the rheumatic disease was not associated with a significant increase in univariate mortality hazards (hazard ratio 1.374, 95% CI: 0.876-2.154), and after adjustment (hazard ratio 1.199, 95% CI: 0.759-1.894) by age, sex and Charlson comorbidity index. The incidence of intensive care unit admission, death, and discharge in the case-control study was comparable between rheumatic and non-rheumatic patients. The presence of rheumatic diseases in SARS-CoV-2-hospitalized patients did not represent an independent risk factor for severe disease or mortality.

Sick leave request following anti-COVID-19 vaccine administration is low among healthcare workers: results from a retrospective cross-sectional monocentric study.

OBJECTIVE: Anti-COVID-19 vaccines were mainly associated with non-serious adverse events (AEs), whose prevalence was reported to be up to 70% in healthcare workers (HCWs). This may lead to sick leave requests, but this impact has never been quantified. This study aimed to investigate the absence from work among HCWs following anti-COVID-19 vaccination. Its association with age and previous COVID-19 infection was also assessed. PATIENTS AND METHODS: This is a retrospective observational cross-sectional study on administrative data about sick leave requests after anti-COVID-19 vaccination. All the HCWs employed at the Niguarda Hospital (Milan, Italy) who received the vaccine from December 27, 2020 to February 28, 2021 were included. RESULTS: In total, 4,088 HCWs received the first dose of the vaccine and 4,043 completed the vaccination cycle. After the first injection, 1.6% of HCWs requested sick leave, while after the second injection, the number of requests significantly increased (+6.1%, p<0.001). A significant increase in sick leave was detected for those who have had SARS-CoV-2 infection after the first injection (+2.3%, p<0.001). After the second dose, a significant increase in sick leave was observed in the 20-30-year-old group compared to >30 years (+3.6%, p=0.017), if HCWs without a history of SARS-CoV-2 infection were considered. CONCLUSIONS: The requests for sick leave among HCWs following the anti-COVID-19 vaccine were limited and higher after the second injection. This may help the management of the human resources when the large-scale administration of the anti-COVID-19 vaccines will involve other categories of workers.

Opioid epidemic spread from Northern and Eastern Europe to Mediterranean Area.

ABSTRACT: The addiction to illicit opioid and the misuse of prescription synthetic opioids pain relievers and fentanyl analogs generated an opioid epidemic in North America over the last two decades that affected public health with a constantly rising number of overdoses deaths. This health treat moved to Europe with a significant increase starting from 2015 involving mainly norther and eastern countries and finally also the Mediterranean area. The "lock down" isolation and economic recession caused by COVID-19 pandemic showed a resurgence in opioid use and harms.

Host factors and history of SARS-CoV-2 infection impact the reactogenicity of BNT162b2 mRNA vaccine: results from a cross-sectional survey on 7,014 workers in healthcare.

OBJECTIVE: This study aimed to improve the post-marketing surveillance on mRNA anti-SARS-CoV-2 vaccines, characterizing the adverse events (AEs) after the first dose of mRNA BNT162b vaccine. The associations between the AEs and individuals' characteristics were explored. PATIENTS AND METHODS: All adult healthcare workers at Niguarda Hospital (Milan, Italy) who were referred for the first dose of vaccine were offered to participate in a cross-sectional survey during the second-dose administration, between 18 January and 7 February 2021. All participants completed a questionnaire about age, gender, weight, height, medical history, concurrent therapies, employment status, previous diagnosis/testing for SARS-CoV-2 infection, and a list of 24 AEs (solicited AEs). The development of at least one solicited AEs was the main outcome. AEs were stratified by the presence of injection-site symptoms, systemic symptoms or both, and the differences between strata were assessed as a secondary outcome. Biometric data and reports of a previous diagnosis of SARS-CoV-2 infection were also explored, as predictors of the main outcome. RESULTS: 7,014 healthcare workers were included. An incidence of 3 per 10.000 persons for serious AEs following the first administration of the mRNA BNT162b vaccine was found. An association between the development of non-serious AEs with young age, female gender, low body mass index, and previous history of SARS-CoV-2 was described. CONCLUSIONS: This real-life study supported data on the safety profile of the BNT162b2 mRNA vaccine. Our findings on the associations between the development of non-serious AEs with some individual characteristics may help physicians and patients make educated and informed medical decisions towards anti-COVID-19 vaccination.

Plasma Wakes Driven by Photon Bursts via Compton Scattering.

Photon bursts with a wavelength smaller than the plasma interparticle distance can drive plasma wakes via Compton scattering. We investigate this fundamental process analytically and numerically for different photon frequencies, photon flux, and plasma magnetization. Our results show that Langmuir and extraordinary modes are driven efficiently when the photon energy density lies above a certain threshold. The interaction of photon bursts with magnetized plasmas is of distinguished interest as the generated extraordinary modes can convert into pure electromagnetic waves at the plasma-vacuum boundary. This could possibly be a mechanism for the generation of radio waves in astrophysical scenarios in the presence of intense sources of high energy photons.

Prospect of Studying Nonperturbative QED with Beam-Beam Collisions.

We demonstrate the experimental feasibility of probing the fully nonperturbative regime of quantum electrodynamics with a 100 GeV-class particle collider. By using tightly compressed and focused electron beams, beamstrahlung radiation losses can be mitigated, allowing the particles to experience extreme electromagnetic fields. Three-dimensional particle-in-cell simulations confirm the viability of this approach. The experimental forefront envisaged has the potential to establish a novel research field and to stimulate the development of a new theoretical methodology for this yet unexplored regime of strong-field quantum electrodynamics.

Ceftaroline modulates the innate immune and host defense responses of immunocompetent cells exposed to cigarette smoke.

BACKGROUND: Cigarette smoke, the principal risk factor for chronic obstructive pulmonary disease (COPD), negatively influences the effectiveness of the immune system's response to a pathogen. The antibiotic ceftaroline exerts immune-modulatory effects in bronchial epithelial cells exposed to cigarette smoke. AIMS AND METHODS: The present study aims to assess the effects of ceftaroline on TLR2 and TLR4 expression, LPS binding and TNF-α and human beta defensin (HBD2) release in an undifferentiated and PMA-differentiated human monocyte cell line (THP-1) exposed or not to cigarette smoke extracts (CSE). TLR2, TLR4, and LPS binding were assessed by flow cytometry, TNF-α and HBD2 release were evaluated by ELISA. RESULTS: The constitutive expression of TLR2 and TLR4 and LPS binding were higher in differentiated compared to undifferentiated THP-1 cells. In undifferentiated THP-1 cells, CSE increased TLR2 and TLR4 protein levels, LPS binding and TNF-α release and reduced HBD2 release and ceftaroline counteracted all these effects. In differentiated THP-1, CSE did not significantly affect TLR2 and TLR4 expression and LPS binding but reduced HBD2 release and increased TNF-α release. Ceftaroline counteracted the effects of CSE on HBD2 release in differentiated THP-1. CONCLUSION: Ceftaroline counteracts the effect of CSE in immune cells by increasing the effectiveness of the innate immune system. This effect may also assist in reducing pathogen activity and recurrent exacerbations in COPD patients.

ß-Boswellic acid, a bioactive substance used in food supplements, inhibits protein synthesis by targeting the ribosomal machinery.

The Boswellia gum resin extracts have been used in traditional medicines because of their remarkable anti-inflammatory properties. Nowadays, these extracts are on the market as food supplements. ß-Boswellic acid (ßBA) is one of the main pentacyclic triterpene components, among the family of BAs, of the Boswellia gum resins. BAs have been broadly studied and are well known for their wide anti-inflammatory and potential anticancer properties. In this paper, a mass spectrometry-based chemoproteomic approach has been applied to characterize the whole ßBA interacting profile. Among the large numbers of proteins fished out, proteasome, 14-3-3 and some ribosomal proteins were considered the most interesting targets strictly connected to the modulation of the cancer progression. In particular, because of their recent assessment as innovative chemotherapeutic targets, the ribosomal proteins were considered the most attractive ßBA partners, and the biological role of their interaction with the natural compound has been evaluated. Copyright © 2016 John Wiley & Sons, Ltd.

Prolyl-isomerase Pin1 controls Notch3 protein expression and regulates T-ALL progression.

Deregulated Notch signaling is associated with T-cell Acute Lymphoblastic Leukemia (T-ALL) development and progression. Increasing evidence reveals that Notch pathway has an important role in the invasion ability of tumor cells, including leukemia, although the underlying molecular mechanisms remain mostly unclear. Here, we show that Notch3 is a novel target protein of the prolyl-isomerase Pin1, which is able to regulate Notch3 protein processing and to stabilize the cleaved product, leading to the increased expression of the intracellular domain (N3IC), finally enhancing Notch3-dependent invasiveness properties. We demonstrate that the combined inhibition of Notch3 and Pin1 in the Notch3-overexpressing human leukemic TALL-1 cells reduces their high invasive potential, by decreasing the expression of the matrix metalloprotease MMP9. Consistently, Pin1 depletion in a mouse model of Notch3-induced T-ALL, by reducing N3IC expression and signaling, impairs the expansion/invasiveness of CD4(+)CD8(+) DP cells in peripheral lymphoid and non-lymphoid organs. Notably, in in silico gene expression analysis of human T-ALL samples we observed a significant correlation between Pin1 and Notch3 expression levels, which may further suggest a key role of the newly identified Notch3-Pin1 axis in T-ALL aggressiveness and progression. Thus, combined suppression of Pin1 and Notch3 proteins may be exploited as an additional target therapy for T-ALL.

Numb-dependent integration of pre-TCR and p53 function in T-cell precursor development.

Numb asymmetrically segregates at mitosis to control cell fate choices during development. Numb inheritance specifies progenitor over differentiated cell fates, and, paradoxically, also promotes neuronal differentiation, thus indicating that the role of Numb may change during development. Here we report that Numb nuclear localization is restricted to early thymocyte precursors, whereas timed appearance of pre-T-cell receptor (pre-TCR) and activation of protein kinase Cθ promote phosphorylation-dependent Numb nuclear exclusion. Notably, nuclear localization of Numb in early thymocyte precursors favors p53 nuclear stabilization, whereas pre-TCR-dependent Numb nuclear exclusion promotes the p53 downmodulation essential for further differentiation. Accordingly, the persistence of Numb in the nucleus impairs the differentiation and promotes precursor cell death. This study reveals a novel regulatory mechanism for Numb function based on its nucleus-cytosol shuttling, coupling the different roles of Numb with different stages of T-cell development.

The diagnostic-therapeutic process. Workflow analysis and risk management with IT tools.

The aim of this work is to study the impact of an Information Technology (IT) tool on clinical risk management and Adverse Drug Events prevention in patient care. In this study we propose the workflow analysis and the application of Failure Modes Effects and Criticality Analysis (FMECA) as potential tools to assess the effectiveness of a specific IT tool in mitigating clinical risk. The study is made up of two different parts: the first one shows the decomposition and representation of the workflow of hospital departments using standardized tools from Project Management. The next phase shows the application of FMECA to the workflow, in order to identify critical issues and evaluate the risk reduction obtained using a specific IT tool, compared to the use of current resources.

Latino values in the context of palliative care: illustrative cases from the Family Focused Grief Therapy trial.

BACKGROUND: Clinicians meet a variety of ethnicities among patients and families in hospice programs. This article focuses on Latino families. METHODS: Within a controlled trial of family therapy in the context of palliative care, 17 families identified as Hispanic. Five were examined qualitatively herein. RESULTS: A synopsis of each family's narrative is presented here. Patterns of strong family loyalty (Familismo), the gender roles of Machismo and Marianismo, the importance of family tradition, expectations about caregiving, and the place of faith and religion emerged as prominent and able potentially to impact on the therapy. CONCLUSIONS: Family therapists need to be thoughtful about cultural issues as they strive to support families.

CT-guided needle biopsy performed with modified coaxial technique in the diagnosis of malignant lymphomas.

PURPOSE: The aim of was study was to evaluate the accuracy of computed tomography (CT)-guided core needle biopsy (CNB) performed by modified coaxial technique as an alternative tool to surgical biopsy in patients with suspected malignant lymphoma. MATERIALS AND METHODS: Between May 2005 and December 2008, 67 CT-guided CNB of deep lesions were performed on 64 patients with suspected malignant lymphoma. In 19 out of 64 patients (29.7%), recurrent lymphoma was suspected. A modified coaxial technique was used in all cases, and multiple samples were obtained for histological and immunohistochemical studies. RESULTS: A diagnosis of malignant lymphomas with specification of subtype according to the World Health Organization (WHO) classification was established in 41/67 cases. Other malignant neoplasms were found in 13/67, lymphoma without subtype specification was diagnosed in 7/67, whereas no conclusive diagnosis could be established in 6/67 cases. Overall diagnostic accuracy was 80.1%. In patients with a final diagnosis of malignant lymphoma, accuracy was 75.9%. No complications occurred. CONCLUSIONS: Percutaneous CT-guided CNB is a safe, effective and reliable tool in the management of lymphomas in patients without superficial lymphadenopathy and can be considered an alternative approach to surgical sampling. The modified coaxial technique represents an effective tool that has a good diagnostic accuracy value with a low complication rate.

Subsets of CD34+ and early engraftment kinetics in allogeneic peripheral SCT for AML.

This study aimed to identify which graft product subset of CD34+ cells might be the most predictive of early hematopoietic recovery following allogeneic peripheral SCT (allo-PBSCT). The relationship between the number of 'mature' subsets of CD34+ cells (CD34+/CD33+, CD34+/CD38+, CD34+/DR+ and CD34+/CD133-) and 'immature' subsets of CD34+ cells (CD34+/CD33-, CD34+/CD38-, CD34+/DR- and CD34+/CD133+) and early neutrophil and platelet engraftment were studied in a homogeneous series (for disease, pre transplant chemotherapy, conditioning regimen and GVHD prophylaxis) of 30 AML patients after allo-PBSCT from HLA-identical siblings. In our experience, the total CD34+/CD133+ cell number was inversely correlated with the days required for the recovery of 0.5 x 10(9)/l neutrophils (r=or-0.82, P=0.02) and platelets of 20 x 10(9)/l (r=or-0.60, P=0.06); this correlation was better than the total CD34+ cell dose and neutrophil (r=or-0.70, P=0.04) and platelet engraftment (r=or-0.56, P=0.07). We suggest that a high number of CD34+/CD133+ PBSC may be associated with faster neutrophil and platelet recovery; these findings may help to predict the repopulating capacity of PBSC in patients after allo-PBSCT, especially when a relatively low number of CD34+ cells is infused.

Poor mobilization is an independent prognostic factor in patients with malignant lymphomas treated by peripheral blood stem cell transplantation.

Haemopoietic stem cell therapy is an increasingly adopted procedure in the treatment of patients with malignant lymphoma. In this retrospective analysis, we evaluated 262 patients, 57 (22%) with Hodgkin's and 205 (78%) with non-Hodgkin's lymphomas (NHL), and 665 harvesting procedures in order to assess the impact of poor mobilization on survival and to determine the factors that may be predictive of CD34(+) poor mobilization. The mobilization chemotherapy regimens consisted of high-dose cyclophosphamide in 92 patients (35.1%) and a high-dose cytarabine-containing regimen (DHAP in 87 patients -(33.2%), MAD in 83 (31.7%)). The incidence of poor mobilizers (<2 x 10(6) CD34(+) cells/kg) was 17.9% overall, with a 10% of very poor mobilizers (< or = 1 x 10(6)/kg). Refractory disease status and chemotherapeutic load (>3 regimens) before mobilization played a negative role and were associated with poor mobilization. Survival analysis of all harvested patients showed an overall survival at 3 years of 71% in good mobilizers vs 33% in poor mobilizers (P=0.002). The event-free survival at 3 years was 23% in poor mobilizers and 58% in good mobilizers (P=0.04). We conclude that in NHL patients, poor mobilization status is predictive of survival.

Increased resistance to oxidation of betalain-enriched human low density lipoproteins.

Betalains are natural pigments recently considered as compounds with potential antioxidative properties. In this work, ex vivo plasma spiking of pure either betanin or indicaxanthin, followed by isolation of low density lipoprotein (LDL), and measurement of its resistance to copper-induced oxidation, has been used to research if these betalains can bind to LDL and prevent oxidation of LDL lipids. When pooled human plasma from 10 healthy volunteers was incubated in the presence of 25-100 microM either betanin or indicaxanthin, incorporation of both compounds in LDL was observed, with a maximum binding of 0.52 +/- 0.08, and 0.51 +/- 0.06 nmoles of indicaxanthin and betanin, respectively, per mg LDL protein. Indicaxanthin-enriched and betanin-enriched LDL were more resistant than homologous native LDL to copper-induced oxidation, as assessed by the elongation of the induction period. The incorporated indicaxanthin, however, appeared twice as effective as betanin in increasing the length of the lag phase, while both compounds did not affect the propagation rate. Both betalains were consumed during the inhibition period of lipid oxidation, and delayed consumption of LDL-beta carotene. Indicaxanthin, but not betanin, prevented vitamin E consumption at the beginning of LDL oxidation, and prolonged the time of its utilization. The resistance of LDL to oxidation when vitamin E and indicaxanthin acted separately in a sequence, was lower than that measured when they were allowed to act in combination, indicating some synergistic interaction between the two molecules. No prooxidant effect over a large concentration range of either betanin or indicaxanthin was observed, when either betalain was added to the LDL system undergoing a copper-induced oxidation. These results show than indicaxanthin and betanin may bind to LDL, and are highly effective in preventing copper-induced lipid oxidation. Interaction with vitamin E appears to add a remarkable potential to indicaxanthin in the protection of LDL. Although molecular mechanisms remain uncompletely understood, various aspects of the action of betanin and indicaxanthin in preventing LDL lipid oxidation are discussed.

High levels of exogenous C2-ceramide promote morphological and biochemical evidences of necrotic features in thyroid follicular cells.

CD95 and ceramide are known to be involved in the apoptotic mechanism. The triggering of CD95 induces a cascade of metabolic events that progressively and dramatically modifies the cell shape by intense membrane blebbing, leading to apoptotic bodies production. Although the CD95 pathway has been abundantly described in normal thyrocytes, the effects of cell permeable synthetic ceramide at morphological and biochemical levels are not fully known. In the present study, we show that thyroid follicular cells (TFC) exposed to 20 microM of C(2)-ceramide for 4 h are characterized by morphological features of necrosis, such as electron-lucent cytoplasm, mitochondrial swelling, and loss of plasma membrane integrity without drastic morphological changes in the nuclei. By contrast, TFC treated with 2 microM of C(2)-ceramide for 4 h are able to accumulate GD3, activate caspases cascade, and induce apoptosis. Furthermore, we provide evidence that 20 microM of C(2)-ceramide determine the destruction of mitochondria and are not able to induce PARP cleavage and internucleosomal DNA fragmentation, suggesting that the apoptotic program is not activated during the death process and nuclear DNA is randomly cleaved as the consequence of cellular degeneration. Pretreatment with 30 microM of zVAD-fmk rescued TFC from 2 microM of C(2)-ceramide-induced apoptosis, whereas, 20 microM of C(2)-ceramide exposure induced necrotic features. Deltapsi(m) was obviously altered in cells treated with 20 microM of C(2)-ceramide for 4 h (75% +/- 3.5%) compared with the low percentage (12.5% +/- 0.4%) of cells with altered Deltapsi(m) exposed to 2 microM of C(2)-ceramide. Whereas, only 20% +/- 1.1% of cells treated with anti-CD95 for 1 h showed altered Deltapsi(m). Additionally, Bax and Bak, two pro-apoptotic members, seem to be not oligomerized in the mitochondrial membrane following ceramide exposure. These results imply that high levels of exogenous ceramide contribute to the necrotic process in TFC, and may provide key molecular basis to the understanding of thyroid signaling pathways that might promote the apoptotic mechanism in thyroid tumoral cells.

Mobilization of peripheral blood stem cells with high-dose cyclophosphamide or the DHAP regimen plus G-CSF in non-Hodgkin's lymphoma.

Our study analyzes the mobilization of hematopoietic stem cells after two chemotherapeutic regimens in non-Hodgkin's lymphoma (NHL) patients. The study included 72 patients with NHL (42 follicular and 30 large cells). The mean age was 37 years (range 17-60). Sixty-four patients (88.9%) had stage III-IV disease. Forty-eight patients (66.7%) had bone marrow involvement. Systemic B symptoms were present in 42 patients (58.3%). Mobilization chemotherapy regimens were randomly assigned as DHAP in 38 patients (52.7%) or cyclophosphamide (CPM) (5 g/m(2)) in 34 (47.2%) and the results of 132 procedures were analyzed. At the time of PBSC mobilization, 46 patients (63.9%) were considered to be responsive (complete remission, partial remission or sensitive relapse) and 26 (36.1%) not responsive (refractory relapse or refractory to therapy). Pre-apheresis CD34+ blood cell count and number of previous chemotherapy treatments were used to predict the total number of CD34+ cells in the apheresis product. The mobilizing regimens (CPM or DHAP) were similar in achieving the threshold CD34+ cell yield, for optimal engraftment. Since DHAP was very effective as salvage treatment, we suggest using DHAP as a mobilizing regimen in patients with active residual lymphoma at the time of stem cell collection.