Teachers' emotional well-being during the SARS-CoV-2 pandemic with long school closures: a large-scale cross-sectional survey in Northern Italy.

OBJECTIVES: This study aimed to evaluate the magnitude of emotional burden on teaching staff during the SARS-CoV-2 pandemic in a significantly impacted region. In addition, the correlates of emotional burden were analysed to enable the design of targeted interventions. STUDY DESIGN: This study was a cross-sectional survey. METHODS: An electronic survey was administered to the teaching staff at public schools and kindergartens in a specific geographical area. Cross-sectional assessments of pandemic-specific variables were performed using the Pandemic Fatigue Scale, the Depression Anxiety Stress Scale (DASS)-21, the Satisfaction with Life Scale, and the Resilient Coping Scale. DASS-21 results were compared with results from a parallel survey that was representative of the local general population. RESULTS: In total, 3251 teaching staff members participated in the survey. Teachers showed a higher emotional burden for depression, anxiety and stress than the general population during the pandemic. According to a linear regression model, this burden is correlated with the language in which the questionnaires were answered, mistrust towards institutions, specific SARS-CoV-2 anxiety, past infection with SARS-CoV-2, avoidance of information about the pandemic and pandemic fatigue; emotional burden was negatively correlated with measures for life satisfaction, resilience and team atmosphere. Some independent variables were shown to contribute differentially to the variance of depression, anxiety or stress. CONCLUSIONS: Emotional distress during the pandemic among teachers is higher than in the general population and correlates with variables that could, at least in principle, be targeted for specific interventions.

Weekend effects on health outcomes and operational efficiency in emergency admissions to general medicine services of the Central Hospital of the Autonomous Province of Bolzano, Italy.

The possibility of higher death rates after admission to hospital during the weekend has been intensively investigated in North America and Northern Europe, while data are almost absent from Southern Europe and other WHOV regions. Increased death rates have not been uniformly confirmed. Differences in hospital care on weekends can vary depending on the reason for hospital admission, place and time. The aim was to verify whether weekend admission from the emergency department to internal medicine services is associated with parameters of operational efficiency in a Northern Italian hospital. A retrospective analysis was performed using hospital administration data of 3,594 admissions in 2016. A total of 287 patients (8.0%) had intensive care unit/IMCU transfers and 218 patients (6.1%) deceased in the hospital. Patients admitted on the weekend were similar to patients admitted during the week across age and gender, while weekend patients were more likely to be admitted on a "bad" day, defined as a day with a median number of admitted patients per day of >10 during the week and >9 on weekend. When adjusting for age and gender, patients admitted on weekend had significantly shorter length of stay compared to patients admitted during the week. In conclusion, emergency weekend admission to an internal medicine service was not associated with worse hospitalization-relevant outcomes in a regional hospital in Italy. Lower length-of-stay when emergency admission was on weekend is suggestive of lower disease severity of patients admitted to internal medicine services than on weekdays. If this represents higher risk of inappropriate hospital admission on weekends requires further study.

Contrast media-induced nephropathy in patients undergoing angiography prior to or during vascular surgery: a systematic review.

Nephropathy induced after administration of contrast medium is an acute and severe complication that is of particular concern in vascular surgery. While patients undergoing coronary procedures have been extensively studied, there is a paucity of data on pre- and intraoperative prevention of contrast-induced nephropathy in vascular surgery patients. There is lack of a robust analysis exploring the additive effect of pre- or intraoperative administration of drugs such as N-acetylcysteine, dopamine and sodium bicarbonate in addition to adequate hydration in patients undergoing angiography prior to or after completion of vascular surgery. A systematic review of contrast-induced nephropathy after angiography in patients undergoing vascular surgery was carried out. Eligible trials were sought by multiple methods, and the pooled odds ratios for contrast-induced nephropathy were computed under a random effects model. Twenty-one publications were identified for screening and 6 studies were included for systematic review. All 6 studies investigated preoperative angiography-related contrast-induced nephropathy; one study also investigated completion angiography. The overall frequency of contrast-induced nephropathy in patients undergoing vascular surgery was 9.2% (79/862). Risk factors for contrast-induced nephropathy identified were age >70 years, high contrast volume, pre-existing renal disease and antihypertensive medication. Two studies found that administration of N-acetylcysteine prior to angiography does not provide added benefit in preventing contrast-induced nephropathy. Advanced age and pre-existing renal and vascular risk factors such as arterial hypertension expose vascular surgery patients to increased risk of contrast-induced nephropathy. Those undergoing completion angiography appear to be at even higher risk, particularly if severely azotemic. Further randomized clinical trials analyzing strategies for preventing contrast-induced nephropathy are needed.

Nosocomial diarrhoea in adult medical patients: the role of Clostridium difficile in a North Italian acute care teaching hospital.

BACKGROUND: The number of patients with severe Clostridium difficile-associated diarrhoea (CDAD) increases. Health care facilities are requested to establish rates of nosocomially acquired CDAD (N-CDAD) to understand the impact of control or prevention measures, and the burden of N-CDAD on health care resources. OBJECTIVE: Aim of the single-center surveillance project was to establish local prevalence rates of N-CDAD in adult acute care medical patients. METHODS: For a period of at least one year, all diarrhoeal stools from inpatients of a general internal medicine ward were tested for Clostridium difficile toxin A. Case record files were retrospectively analysed and questionnaires were completed for patients with positive stool assays who met the case definitions. RESULTS AND DISCUSSION: During the surveillance period, 2,610 medical patients had been acutely hospitalized. Stools had been submitted to the hospital laboratory from 163 patients (6.2%) because of diarrhoea and were screened for Clostridium difficile cytotoxin. Complete data sets were available for analysis from 150 patients. Of 137 identified potential cases, 77 (56.2%) met the case definitions for nosocomial diarrhoea. Thirteen of the patients with nosocomial diarrhoea (16.9%) were detected positive by the Clostridium difficile toxin A assay. The overall prevalence of N-CDAD among inpatients was 8.7 cases/100 diarrhoeal stools. The mean number ofN-CDAD cases was 62.3 cases/100,000 patient days and 5 cases/1,000 patient admissions. The mean age of N-CDAD patients was 79.4 years (range 71 to 92). All patients were given broad-spectrum antibiotics before acute diarrhoea developed. Four patients died for reasons not directly related to N-CDAD which confirms increased disease severity as an important risk factor. CONCLUSIONS: This single-center surveillance project, which established N-CDAD rates at frequencies currently reported from international surveys, is useful as benchmark and will help in understanding patterns and impact of N-CDAD at the regional level.

Antithrombin concentrate use in disseminated intravascular coagulation of sepsis: meta-analyses revisited.

Recently, two meta-analyses examined the effect of antithrombin on mortality in patients with sepsis and disseminated intravascular coagulation (DIC) with diverging results. In the meta-analysis observing no significant survival effect of antithrombin, the results of a large trial were included under the assumption that all 2314 participants of the trial had sepsis and DIC, which according to post hoc analyses was not the case. To the other meta-analysis reporting beneficial effect, the same trial contributed only those 229 patients that had confirmed sepsis-induced DIC. Replacing the mixed sepsis patient group with and without DIC with the group of sepsis patients with confirmed DIC provides evidence for a beneficial intervention effect of antithrombin also in the meta-analysis that reported no beneficial effect of antithrombin on mortality. This revised result does not change the overall conclusion that the quantity and quality of evidence supporting the use of antithrombin in sepsis patients with DIC is low.

Monocyte haptotaxis induced by the RANTES chemokine.

BACKGROUND: Soluble mediators and inducible cell-surface molecules coordinate the ordered cascade of events giving rise to inflammation. The specific mechanisms underlying the attraction of antigen-specific cells into a site of inflammation remain sketchy, however. In particular, it is unclear how chemoattractants cause rapidly moving immune cells to adhere to the blood vessel wall and to enter inflamed tissues. RESULTS: Here we show that RANTES, a potent chemo-attractant for monocytes and T lymphocytes, is inducibly expressed within an inflamed organ, binds to endothelial cells, and promotes haptotaxis, the migration of cells induced by surface-bound gradients. CONCLUSION: These findings lead us to propose a model for the role of RANTES in the migration of antigen-specific immune cells into an inflammatory site.

Priming of polymorphonuclear neutrophils by atrial natriuretic peptide in vitro.

In ischemia-reflow states of coronary artery disease, the activation of PMN precedes the initiation of tissue damage. Release of atrial natriuretic peptide (ANP) from myocytes occurs within minutes after the onset of myocardial ischemia, which suggests a possible role of ANP in PMN activation. To investigate this possibility, we tested the effects of ANP on functions of PMN in vitro. ANP is a potent signal for priming the PMN respiration burst to secrete superoxide anion. Phorbol 12-myristate 13-acetate, opsonized zymosan, or FMLP could all be used as triggering stimuli to demonstrate the priming of PMN activation by ANP. Only ANP fragments 1-28 and 7-28 enhanced respiration burst activity but identical preparations of ANP fragments 13-18 or 1-11 failed to do so. This structure-activity relationship is typical of receptors for ANP found in other tissues. In addition, ANP stimulated the release of beta-glucuronidase From PMN triggered by FMLP. The observed inhibition by ANP of FMLP-stimulated chemotaxis of PMN may be due to their enhanced adhesiveness. These data show that a classic cardiac hormone is involved in regulating important functional activities of PMN. These data support the possibility that ANP could act as a preinflammatory substance in ischemia-reperfusion states and myocardial necrosis.

Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation.

BACKGROUND: Disseminated intravascular coagulation (DIC) is a serious complication of sepsis that is associated with a high mortality. OBJECTIVES: Using the adapted International Society on Thrombosis and Haemostasis (ISTH) diagnostic scoring algorithm for DIC, we evaluated the treatment effects of high-dose antithrombin (AT) in patients with severe sepsis with or without DIC. PATIENTS AND METHODS: From the phase III clinical trial in severe sepsis (KyberSept), 563 patients were identified (placebo, 277; AT, 286) who did not receive concomitant heparin and had sufficient data for DIC determination. RESULTS: At baseline, 40.7% of patients (229 of 563) had DIC. DIC in the placebo-treated patients was associated with an excess risk of mortality (28-day mortality: 40.0% vs. 22.2%, P < 0.01). AT-treated patients with DIC had an absolute reduction in 28-day mortality of 14.6% compared with placebo (P = 0.02) whereas in patients without DIC no effect on 28-day mortality was seen (0.1% reduction in mortality; P = 1.0). Bleeding complications in AT-treated patients with and without DIC were higher compared with placebo (major bleeding rates: 7.0% vs. 5.2% for patients with DIC, P = 0.6; 9.8% vs. 3.1% for patients without DIC, P = 0.02). CONCLUSIONS: High-dose AT without concomitant heparin in septic patients with DIC may result in a significant mortality reduction. The adapted ISTH DIC score may identify patients with severe sepsis who potentially benefit from high-dose AT treatment.

The acute-phase protein alpha 1-antitrypsin inhibits transferrin-receptor binding and proliferation of human skin fibroblasts.

Transferrin (Tf) is required for proliferation of most cells, because cellular iron uptake is mainly mediated by binding of Tf to its specific cell surface receptors (TfR). The acute-phase protein alpha 1-antitrypsin (alpha 1-AT) completely inhibits binding of diferric Tf to TfRs on human skin fibroblasts in a dose-dependent fashion. The inhibition is competitive as proved in equilibrium saturation binding and kinetic studies. In saturation binding experiments alpha 1-AT apparently increased the dissociation constant (KD), but did not change the maximal density of binding sites (Bmax). As shown in kinetic studies, this reduction of the affinity of Tf to its receptor caused by alpha 1-AT was due to a decrease of the association rate constant (k + 1), whereas the dissociation rate constant (k - 1) remained unchanged. Furthermore, alpha 1-AT almost completely prevented internalization of the Tf-TfR complex. These interactions demonstrated biological implication, as alpha 1-AT reduced the proliferation of human fibroblasts up to maximal 30% of control. The inhibitory potency of alpha 1-AT was already seen in physiologic concentrations; the maximal effect, however, was achieved at concentrations above the normal range, which are attained in the course of inflammation and infection. Therefore, we suppose that alpha 1-AT as an endogenous factor modulates the complex mechanism of fibrogenesis not only by its known antiproteolytic function but also by inhibiting the proliferation of fibroblasts.

Chronic infections and the risk of carotid atherosclerosis: prospective results from a large population study.

BACKGROUND: Chronic infections have been implicated in the pathogenesis of atherosclerosis, yet from an epidemiological perspective, this concept remains controversial. METHODS AND RESULTS: The Bruneck Study is a prospective population-based survey on the pathogenesis of atherosclerosis. In 826 men and women 40 to 79 years old (1990 baseline), 5-year changes in carotid atherosclerosis were thoroughly assessed by high-resolution duplex scanning. The presence of chronic respiratory, urinary tract, dental, and other infections was ascertained by standard diagnostic criteria. Chronic infections amplified the risk of atherosclerosis development in the carotid arteries. The association was most pronounced in subjects free of carotid atherosclerosis at baseline (age-/sex-adjusted odds ratio [95% CI] for any chronic infection versus none, 4.08 [2.42 to 6.85]; P:<0.0001) and applied to all types of chronic (bacterial) infections. It remained independently significant after adjustment for classic vascular risk attributes and extended to low-risk individuals free of conventional risk factors. Among subjects with chronic infections, atherosclerosis risk was highest in those with a prominent inflammatory response. Markers of systemic inflammation, such as soluble adhesion molecules and circulating bacterial endotoxin, and levels of soluble human heat-shock protein 60 and antibodies to mycobacterial heat-shock protein 65 were elevated in subjects with chronic infections and predictive of an increased risk of atherosclerosis. CONCLUSIONS: The present study provides solid evidence for a role of common chronic infections in human atherogenesis. Induction of systemic inflammation and autoimmunity may be potential pathophysiological links.

Increased levels of serum neopterin and decreased production of neutrophil superoxide anions in chronic heart failure with elevated levels of tumor necrosis factor-alpha.

OBJECTIVES: The purpose of this study was to examine the role of tumor necrosis factor-alpha and tetrahydrobiopterin and superoxide anion release from neutrophils in severe chronic heart failure. BACKGROUND: Previous studies have demonstrated elevated production of tumor necrosis factor-alpha and free radical-induced endothelial cell damage in severe heart failure. METHODS: Plasma and serum levels of immunoreactive interleukin-1, interleukin-6, interferon-gamma, neopterin and tumor necrosis factor-alpha and the release of superoxide anions from circulating neutrophils both at basal conditions and after triggering with f-Met-Leu-Phe or phorbol 12-myristate 13-acetate were measured in 16 patients with severe heart failure and in 11 healthy control subjects. RESULTS: Circulating levels of tumor necrosis factor-alpha and neopterin were elevated in patients with heart failure compared with values in control subjects. A significant correlation between the two was found. Basal and phorbolester-triggered release of oxygen radicals from neutrophils was not affected in patients with heart failure. However, formylpeptide-stimulated release of oxygen radicals by neutrophils was significantly reduced. CONCLUSIONS: Suppressed neutrophil function in patients with heart failure exhibiting elevated levels of tumor necrosis-alpha factor may indicate self-protection against the deleterious effects of neutrophil-derived oxygen radicals. Through induction of tetrahydrobiopterin synthesis (as reflected by increased neopterin), tumor necrosis factor-alpha may affect nitric oxide synthesis.

Association of endotoxemia with carotid atherosclerosis and cardiovascular disease: prospective results from the Bruneck Study.

OBJECTIVES: Focus of the current study was on the significance of bacterial endotoxin, which shows a variety of pro-atherogenic properties and may occur at high concentration in the circulation of infected subjects. BACKGROUND: The possibility of an infectious risk factor in atherogenesis and cardiovascular disease has stimulated research interest, but the nature of such process remains obscure. METHODS: We measured plasma endotoxin levels (LAL assay) in a random population of 516 men and women 50 to 79 years old at the 1990 baseline evaluation (Bruneck Study). End points of this prospective survey were incident (early) atherosclerosis in the carotid arteries as assessed with high-resolution Duplex ultrasound (five-year follow-up rate, 98%) and incident cardiovascular disease (follow-up rate, 100%). RESULTS: Median endotoxin concentration amounted to 14.3 pg/ml (range, 6.0 to 209.2 pg/ml). Subjects with levels beyond 50 pg/ml (90th percentile) faced a threefold risk of incident atherosclerosis (odds ratio [95% confidence interval] 2.9 [1.4-6.3]; p < 0.01). The risk associated with high endotoxin was most pronounced in subjects with chronic infections and in current and ex-smokers. Notably, smokers with low endotoxin levels and nonsmokers did not differ in their atherosclerosis risk, whereas smokers with high levels almost invariably developed new lesions. All findings emerged as independent of vascular risk factors. Similar results were obtained for incident cardiovascular disease. CONCLUSIONS: The current study yields first epidemiologic evidence that endotoxemia constitutes a strong risk factor of early atherogenesis in subjects with chronic or recurrent bacterial infections and a link in the association between cigarette smoking and atherosclerotic disease.

Neuropeptides and the immune system: focus on dendritic cells.

Neuropeptides are small, biologically active peptides derived from the central and peripheral nervous system. It is increasingly clear that besides their function as neurotransmitters, these peptides have an influence on almost all body functions including the immune system. Since dendritic cells are the most efficient antigen-presenting cells that stimulate naive T cells, thus promoting adaptive immunity, it is not surprising that interactions between neuropeptides and dendritic cells take place. The current review addresses several aspects of dendritic cell-related neuroimmunology and focuses on the role of neuropeptides as immunomodulators. Moreover, we present a novel concept of neuropeptide-mediated regulation of dendritic cell migration. The importance of chemokines in immunity is generally accepted. It may be that not enough attention has been paid to the possible role of nervous system-derived peptides in regulating immune reactions.

Signaling in neuropeptide-induced migration of human eosinophils.

At inflammatory sites, leukocytes may confront multiple, competing chemoattractive signals. We compared the chemotactic potencies of several sensory neuropeptides with regard to signal transduction pathways in eosinophils. Eosinophils were enriched using magnetic cell sorting and migration was assayed in a Boyden microchemotaxis chamber. We found stimulatory effects of substance P, calcitonin gene-related peptide (CGRP), secretoneurin, vasoactive intestinal peptide (VIP), and secretin on eosinophil migration. Actions of VIP are predominantly mediated via VIP receptor type I. Migration toward secretoneurin, VIP, and secretin was blocked by a phosphodiesterase inhibitor, which, in contrast failed to affect substance P- and CGRP-induced eosinophil chemotaxis. Wortmannin blunted the migratory responses induced by all neuropeptides tested and substance P-induced effects on eosinophils were tyrphostin-23-sensitive. We conclude that substance P, CGRP, secretoneurin, and VIP/secretin stimulate eosinophil migration involving wortmannin-sensitive enzymes. Moreover, secretoneurin and VIP/secretin require additional activation of phosphodiesterases to stimulate eosinophil migration.

Enhanced secretion of immunoreactive bombesin by alveolar macrophages exposed to silica.

Bombesin has recently been identified in alveolar macrophages (AM). Since this peptide has been shown to stimulate fibroblast growth in culture, we wished to determine whether AM exposed to the fibrogenic particle silica in vivo were capable of secreting more bombesin than AM recovered after instilling inert carbon particles to the lung. Rats received 10 mg of either carbon or silica by intratracheal injection and were killed at 3 days or 6 weeks. Both particles induced a rapid inflammatory response, and normal levels of immunoreactive bombesin were measured in lung lavage fluid and in freshly recovered macrophages from all rats. However, incubation of normal AM for 4 h in serum free medium produced a significant increase in bombesin levels measured in supernatants. Bombesin in supernatants of AM cultured after recovery from rats exposed to carbon was at the control value, while AM recovered after silica exposure in vivo secreted increased amounts of bombesin when cultured. Cells recovered 6 wk after instilling silica to the lung and cultured for 4 h secreted 50% more bombesin than control AM. At this time, hydroxyproline measured in the silica-injected lungs was also significantly higher than in controls or carbon-injected rats. These results indicate that AM recovered from lungs after exposure to silica secrete increased amounts of bombesin during the development of pulmonary fibrosis.

Different patterns of deactivation of chemotaxis and haptotaxis of human peripheral blood mononuclear leukocytes by soluble and surface-bound attractants.

Soluble mediators and inducible cell-surface and matrix-bound molecules coordinate the cascade of events giving rise to leukocyte emigration. Knowledge of the specific mechanisms underlying the attraction of cells into a local site, however, remains sketchy. In particular, it is unclear how chemoattractants cause rapidly moving immune cells to adhere to the blood vessel wall and to enter tissues. Here we show that the neuroendocrine human growth hormone, a chemoattractant for monocytes and lymphocytes in vitro, promotes haptotaxis, the migration of the cells induced by surface-bound gradients. Combination of soluble growth hormone with soluble attractants, RANTES or formyl peptide, deactivates the migratory responses, as do combinations of surface-bound growth hormone with surface-bound RANTES or formyl peptide. In contrast, exposure of mononuclear leukocytes to combinations of soluble chemotactic with surface-bound haptotactic gradients of attractants does not deactivate migration. The findings suggest that growth hormone may act as haptotactic agent, on the one hand, and that soluble attractants do not appear to affect haptotaxis when acting in concert with a surface-bound attractant, on the other. This observation may have implications for the differential regulation of leukocyte accumulation in the vessel wall at systemic and local sites.

Proliferation and differentiation of human erythropoiesis in vitro: effect of different human lipoprotein species.

In order to permit erythroid proliferation in agar, a serum-free system was developed based on McCoy's 5A medium at pH 8.0, containing deionized and delipidated bovine serum albumin, iron-saturated transferrin, and crude erythropoietin (step III). Addition of the entire complement of serum lipoproteins, termed lipoprotein fraction I (density, less than 1.21 g/ml), increased the number of erythroid colony-forming units and erythroid burst-forming units to numbers indistinguishable from those observed with media containing serum. Moreover, terminal differentiation occurred to fully hemoglobinized normoblasts and even mature erythrocytes. Under these conditions, the erythropoietin dose-response curve obtained when not using serum was comparable to that with serum. Colony formation also displayed a linear relationship to seeding densities down to limiting dilutions. For differential analysis of the main density lipoprotein fractions, sequential ultracentrifugation was performed to isolate very low-density lipoproteins, low-density lipoproteins (LDL), high-density lipoproteins2 (HDL2), and HDL3, which were then added individually to serum-free cultures. Of the main lipoprotein classes, LDL exhibited the most proliferative capacity, followed by HDL2 and HDL3. Our findings indicate that when serum is substituted by well defined compounds including highly purified lipoprotein fractions, a serum-like proliferation and differentiation of human erythropoietic progenitor cells in agar can be obtained.