Hemodynamic Evaluation of Nonselective \u3b2-Blockers in Patients with Cirrhosis and Refractory Ascites

BACKGROUND:Nonselective \u3b2-blockers (NSBB) have been associated with increased incidence of paracentesis-induced circulatory dysfunction (PICD) and reduced survival in patients with cirrhosis and refractory ascites. AIM:To prospectively evaluate a hemodynamic response to NSBB in cirrhotics listed for liver transplantation with refractory ascites undergoing large volume paracentesis (LVP). METHODS:Patients with cirrhosis and refractory ascites, with an indication to start NSBB in primary prophylaxis for variceal bleeding, were enrolled. During two consecutive LVP, while being, respectively, off and on NSBB, cardiac output (CO), systemic vascular resistances (SVR), peripheral vascular resistances (PVR), and plasma renin activity (PRA) were noninvasively assessed. RESULTS:Seventeen patients were enrolled, and 10 completed the study. Before NSBB introduction, SVR (1896 to 1348\u2009dyn\ub7s\ub7cm-5; p = 0.028) and PVR (47 to 30\u2009mmHg\ub7min\ub7dl\ub7ml-1; p = 0.04) significantly decreased after LVP, while CO showed an increasing trend (3.9 to 4.5\u2009l/m; p = 0.06). After NSBB introduction, LVP was not associated with a significant increase in CO (3.4 to 3.8\u2009l/m; p = 0.13) nor with a significant decrease in SVR (2002 versus 1798\u2009dyn\ub7s\ub7cm-5; p = 0.1). Incidence of PICD was not increased after NSBB introduction. CONCLUSION:The negative inotropic effect of NSBB was counterbalanced by a smaller decrease of vascular resistances after LVP, probably due to splanchnic \u3b22-blockade. This pilot study showed that NSBB introduction may be void of detrimental hemodynamic effects after LVP in cirrhotics with refractory ascites

Synergistic antitumour activity of RAF265 and ZSTK474 on human TT medullary thyroid cancer cells

Medullary thyroid cancer (MTC) is an aggressive malignancy responsible for up to 14% of all thyroid cancer-related deaths. It is characterized by point mutations in the rearranged during transfection (RET) proto-oncogene. The activated RET kinase is known to signal via extracellular signal regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K), leading to enhanced proliferation and resistance to apoptosis. In the present work, we have investigated the effect of two serine/threonine-protein kinase B-Raf (BRAF) inhibitors (RAF265 and SB590885), and a PI3K inhibitor (ZSTK474), on RET-mediated signalling and proliferation in a MTC cell line (TT cells) harbouring the RETC634W activating mutation. The effects of the inhibitors on VEGFR2, PI3K/Akt and mitogen-activated protein kinases signalling pathways, cell cycle, apoptosis and calcitonin production were also investigated. Only the RAF265+ ZSTK474 combination synergistically reduced the viability of treated cells. We observed a strong decrease in phosphorylated VEGFR2 for RAF265+ ZSTK474 and a signal reduction in activated Akt for ZSTK474. The activated ERK signal also decreased after RAF265 and RAF265+ ZSTK474 treatments. Alone and in combination with ZSTK474, RAF265 induced a sustained increase in necrosis. Only RAF265, alone and combined with ZSTK474, prompted a significant drop in calcitonin production. Combination therapy using RAF265 and ZSTK47 proved effective in MTC, demonstrating a cytotoxic effect. As the two inhibitors have been successfully tested individually in clinical trials on other human cancers, our preclinical data support the feasibility of their combined use in aggressive MTC

Effect of Maternal Smoking on Breast Milk Interleukin-1α, β-Endorphin, and Leptin Concentrations

Tobacco smoke is immunotoxic, but the effect of smoking on the immunologic function of the mammary gland of mothers who smoke cigarettes (“smoker mothers”) has not been studied. Our objective was to test, in smoker mothers, the colostral and transitional milk concentrations of interleukin-(IL)1α. The immunomodulators β-endorphin and leptin were also tested. Pregnant women who self-identified as smokers (≥ 5 cigarettes per day through pregnancy) or nonsmokers were recruited for study participation. The study population included 42 smoker and 40 non-smoker nursing mothers, with otherwise uncomplicated gestation, delivery, and puerperium, who were breast-feeding ad libitum their healthy neonates. Colostrum was obtained on the third postpartum day at 0900 hr and transitional milk on the 10th postpartum day at 0900 hr. IL-1α concentrations were significantly reduced in the colostrum of smoker mothers compared with nonsmoker mothers (p < 0.01). Colostral β-endorphin and leptin concentrations were comparable. No significant differences were found between smoker and nonsmoker lactating mothers in transitional milk concentrations of IL-1α, β-endorphin, and leptin. Moreover, β-endorphin and leptin concentrations were significantly reduced in transitional milk samples compared with colostrum of both smoker and nonsmoker mothers (p < 0.05); also, IL-1α transitional milk concentrations were reduced compared with colostrum, but without any significance. This analysis shows that maternal smoking alters the colostral milk levels of the proinflammatory cytokine IL-1α. The altered postnatal provision of alternative source of the proinflammatory cytokine IL-1α adds understanding to how breast-feeding could be nonprotective against infections among the neonates nursed by smoker mothers

New insights into SARS-CoV-2 Lumipulse G salivary antigen testing: accuracy, safety and short TAT enhance surveillance

Objectives The rapid, accurate and safe detection of SARS-CoV-2 is the key to improving surveillance and infection containment. The aim of the present study was to ascertain whether, after heat/chemical inactivation, SARS-CoV-2 N antigen chemiluminescence (CLEIA) assay in saliva remains a valid alternative to molecular testing. Methods In 2022, 139 COVID-19 inpatients and 467 healthcare workers were enrolled. In 606 self-collected saliva samples (Salivette), SARS-CoV-2 was detected by molecular (TaqPath rRT-PCR) and chemiluminescent Ag assays (Lumipulse G). The effect of sample pre-treatment (extraction solution-ES or heating) on antigen recovery was verified. Results Salivary SARS-CoV-2 antigen assay was highly accurate (AUC=0.959, 95% CI: 0.943-0.974), with 90% sensitivity and 92% specificity. Of the 254 antigen positive samples, 29 were false positives. We demonstrated that heterophilic antibodies could be a cause of false positive results. A significant antigen concentration decrease was observed after ES treatment (p=0.0026), with misclassification of 43 samples. Heat had a minimal impact, after treatment the correct classification of cases was maintained. Conclusions CLEIA SARS-CoV-2 salivary antigen provides accurate, timely and high-throughput results that remain accurate also after heat inactivation, thus ensuring a safer work environment. This supports the use of salivary antigen detection by CLEIA in surveillance programs

THE NATURAL HISTORY OF AUTOIMMUNE ADDISON'S DISEASE FROM THE DETECTION OF AUTOANTIBODIES TO DEVELOPMENT OF THE DISEASE: A LONG FOLLOW-UP STUDY ON 143 PATIENTS

Adrenal cortex autoantibodies (ACA) and/or 21-hydroxylase (21OHAb) are markers of autoimmune Addison's disease (AAD) and progression to overt AAD. The reported cumulative risk of developing AAD varies from 0-90% in different studies. Aim To assess the predictive value of different parameters for progression towards AAD in ACA and/or 21OHAb-positive patients with autoimmune polyendocrine syndromes (APS). Materials and Methods 29 patients with APS-1 and 114 patients with APS-2 or APS-4, were followed-up for a median of 10 years (range 6 months-33 years) and assessed by ACTH test. The risk of AAD was estimated according to age, gender, stage of adrenal dysfunction, associated diseases and antibody titer. Univariate and multivariate Cox proportional hazard models were used for statistical analysis. Results The cumulative risk (CR) of developing AAD was higher in APS-1 patients (94.2%) compared to patients with APS-2/APS-4 (38.7%). The CR was high in both males and females with APS-1 patients, while in patients with APS-2/APS-4 it was high only in males. Stage 1 (increased plasma renin) for patients with APS-1 and Stage 2 (no response of cortisol to ACTH-test) for patients with APS-2/APS-4 were established as the points of no return in the progression to AAD. Adjusted hazard ratio analyses by multivariate Cox model for AAD showed that gender, diseases, adrenal function were independent risk factors for developing clinical AAD. The risk of developing clinical AAD appears to subside after 19 years of follow up. Conclusions A model for estimating the probability to survive free of AAD has been developed and should be a useful tool in designing appropriate follow-up intervals and future therapeutic strategies

Utilization management: a European perspective.

Utilization management (UM) in health care, based on the collection, assessment and monitoring of data pertaining to patient services and treatment, ultimately assures efficiency and effectiveness. The central role of laboratory services in modern medicine created the need to utilize UM programs in clinical laboratories in order to reduce costs, enhance efficiency and improve on quality for patients. Some UM programs have focused on improving efficiency by reducing the cost per test. Consolidation and networking have been proposed as opportunities to increase test volumes, thus achieving economy of scale, and a better ratio between test volumes and fulltime equivalent (FTE) staff. However, little evidence is available in the literature to demonstrate the efficiency of these models, and concern has been expressed regarding the possible increase in pre-analytical errors and the loss of efficient communication between clinicians and laboratory professionals. In Europe, we have seen an increasing emphasis on the importance of demand management strategies as the key to reducing costs and improving on quality in laboratory medicine. The cost of inappropriate requesting includes not only test consumables and reagents, but also additional consultations, treatment and investigations. A number of studies in literature describe strategies and initiatives designed to change and improve test requesting, but the following two items are mandatory for real improvement: a) the active involvement of requesting physicians and other stakeholders, including patients; and b) the use of combined interventions instead of a single strategy. Therefore, the use of approaches for demand management that considers pre-, within- and post-laboratory initiatives is on the increase in clinical laboratories throughout Europe

Clinical efficiency of in vitro and in vivo tests for allergic diseases.

Abstract BACKGROUND: Specific serum IgE determination is widely used in the diagnosis of IgE-mediated allergic diseases but the relative merits of in vitro measurement of IgE antibody in comparison to in vivo skin tests are still debated. OBJECTIVE: The aim of this study was to investigate the clinical efficiency of a "second generation" technique for in vitro analysis of IgE antibody (Pharmacia CAP System). METHODS: Eighty-six patients with suspected inhalant and/or food allergies and 20 asymptomatic subjects for a total of 655 tests were evaluated. Sera with divergent results between in vitro and in vivo techniques were further analyzed by using ImmunoCAP inhibition and immunoblotting. For the calculation of sensitivity and specificity of both in vitro and in vivo tests we considered as true value (reference value) either the concordant results or, in case of discordance, the datum confirmed by ImmunoCAP inhibition or immunoblot (ie, vitro positive, vivo negative, ImmunoCAP inhibition positive; true result: positive). RESULTS: The obtained results demonstrate that the in vitro results correlate well in terms of specificity and sensitivity to this new reference standard. In particular a higher specificity for Pharmacia CAP System in comparison to in vivo skin prick test for grass pollens and a better sensitivity for mites and cat allergens were found. CONCLUSIONS: Our results suggest that the in vitro "second generation" testing provides reliable results in all clinical situations

Shop for quality or quantity? Volumes and costs in clinical laboratories.

BACKGROUND: The increasing need to reduce the costs of providing diagnostic laboratory services has prompted initiatives based on the centralization and consolidation of laboratory facilities. However, the majority of papers and experiences reported in literature focus on "cost per test" thus overlooking the real value of a laboratory service, which requires more complex economic evaluations, such as cost-benefit, cost-effectiveness, and cost-utility analysis. It is important to perform cost analysis, which is no mean feat, by taking into consideration all variables affecting the final and true cost per test. METHODS: The present study was conducted in order to evaluate the costs of delivering laboratory services in 20 Italian clinical laboratories using a widely accepted methodology, the so-called "activity-based costing analysis". RESULTS: The finding of a trend towards a decrease in total costs - due to an increase in test volumes - attained statistical significance only for quantities of up to about 1,100,00 tests per year. For 1,800,00 tests and more, the cost per test appeared to range from 1.5 to 2.0 € irrespective of the different volumes. Regarding the relationship between volumes and number of staff, there is an evident linear relationship between the number of senior staff and volumes, whereas this trend is not observed in the case of medical technologists, the degree and type of automation strongly affecting this variable. CONCLUSIONS: The findings made in the present study confirm that the relationship between volumes and costs is not linear; since it is complex, numerous variables should be taken into account