Plasma membrane gamma-glutamyltransferase activity facilitates the uptake of vitamin C in melanoma cells.

Adequate cellular transport of ascorbic acid (AA) and its oxidation product dehydroascorbate (DHA) is assured through specific carriers. It was shown that vitamin C is taken up as DHA by most cell types, including cancer cells, via the facilitative GLUT transporters. Thus, AA oxidation to DHA can be considered a mechanism favoring vitamin C uptake and intracellular accumulation. We have investigated whether such an AA-oxidizing action might be provided by plasma membrane g-glutamyltransferase (GGT), previously shown to function as an autocrine source of prooxidants. The process was studied using two distinct human metastatic melanoma clones. It was observed that the Me665/2/60 clone, expressing high levels of membrane GGT activity, was capable of effecting the oxidation of extracellular AA, accompanied by a marked increase of intracellular AA levels. The phenomenon was not observed with Me665/2/21 cells, possessing only traces of membrane GGT. On the other hand, AA oxidation and stimulation of cellular uptake were indeed observed after transfection of 2/21 cells with cDNA coding for GGT. The mechanism of GGTmediated AA oxidation was investigated in acellular systems, including GGT and its substrate glutathione. The process was observed in the presence of redox-active chelated iron(II) and of transferrin or ferritin, i.e., two physiological iron sources. Thus, membrane GGT activity—often expressed at high levels in human malignancies—can oxidize extracellular AA and promote its uptake efficiently

Failure to rescue as a source of variation in hospital mortality after rectal surgery: The Italian experience

INTRODUCTION: Failure to rescue (FTR) patients from postoperative complications could contribute to the variability in surgical mortality seen among hospitals with different volumes. We sought to examine the impact of complications and FTR on mortality following rectal surgery. METHODS: The National Italian Hospital Discharge Dataset allowed to identify 75,280 patients who underwent rectal surgery between 2002 and 2014. Hospital volume was stratified into tertiles. Rates of major complications, FTR from complications and mortality following rectal surgery were compared. RESULTS: During the study period, both the incidence of complications (2002, 23.7% versus 2014, 21.2%), and FTR decreased overtime (2002, 6.9% versus 2014, 3.8%) (both P\u202f<\u202f0.001). The complication rate was 24.4% in low-, 21.6% in intermediate- and 20.4% in high-volume hospitals (P\u202f<\u202f0.001). Complications were less common in minimally invasive surgery (MIS) versus open cases (18.2% versus 23.2%; P\u202f<\u202f0.001). The most frequent complications included prolonged ileus or small bowel obstruction (5.3%), and anemia requiring blood transfusions (5.3%). The rate of FTR was 5.5%, 5.6% and 3.7% for low-, intermediate- and high-volume hospitals, respectively (P\u202f<\u202f0.001). FTR after MIS was 2.6% vs. 5.5% after open surgery (P\u202f<\u202f0.001). After accounting for patient and hospital characteristics, patients treated at low-volume hospitals were 23% more likely to die after a complication, compared to patients at high-volume hospitals (OR 1.23, 95%CI 1.13-1.33). CONCLUSIONS: Hospital volume is the strongest predictor of complication and FTR. The reduction in mortality in high-volume hospitals could be determined by the better ability to rescue patients. These findings support the centralization policy of rectal cancer treatment

Remote Technology-Based Training Programs for Children with Acquired Brain Injury: A Systematic Review and a Meta-Analytic Exploration

Introduction. Multidisciplinary rehabilitation interventions are considered to be a need for children with acquired brain injury (ABI), in order to remediate the important sequelae and promote adjustment. Technology-based treatments represent a promising field inside the rehabilitation area, as they allow delivering interventions in ecological settings and creating amusing exercises that may favor engagement. In this work, we present an overview of remote technology-based training programs (TP) addressing cognitive and behavioral issues delivered to children with ABI and complement it with the results of a meta-analytic exploration. Evidence Acquisition. We performed the review process between January and February 2019. 32 studies were included in the review, of which 14 were further selected to be included in the meta-analysis on TP efficacy. Evidence Synthesis. Based on the review process, the majority of TP addressing cognitive issues and all TP focusing on behavioral issues were found to be effective. Two meta-analytic models examining the means of either cognitive TP outcomes or behavioral TP outcomes as input outcome yielded a nonsignificant effect size for cognitive TP and a low-moderate effect size for behavioral TP. Additional models on outcomes reflecting the greatest beneficial effects of TP yielded significant moderate effect sizes for both types of TP. Nevertheless, consistent methodological heterogeneity was observed, pointing to cautious interpretation of findings. A subgroup analysis on visuospatial skill outcomes showed a smaller yet significant effect size of cognitive TP, with low heterogeneity, providing a more reliable estimation of overall cognitive TP effects. Conclusions. Promising results on remote cognitive and behavioral TP efficacy emerged both at the review process and at the meta-analytic investigation. Nevertheless, the high heterogeneity that emerged across studies prevents us from drawing definite conclusions. Further research is needed to identify whether specific training characteristics and population subgroups are more likely to be associated with greater training efficacy

Relationship between hospital volume and short-term outcomes: A nationwide population-based study including 75,280 rectal cancer surgical procedures

There is growing interest on the potential relationship between hospital volume (HV) and outcomes as it might justify the centralization of care for rectal cancer surgery. From the National Italian Hospital Discharge Dataset, data on 75,280 rectal cancer patients who underwent elective major surgery between 2002 and 2014 were retrieved and analyzed. HV was grouped into tertiles: low-volume performed 1-12, while high-volume hospitals performed 33+ procedures/year. The impact of HV on in-hospital mortality, abdominoperineal resection (APR), 30-day readmission, and length of stay (LOS) was assessed. Risk factors were calculated using multivariate logistic regression. The proportion of procedures performed in low-volume hospitals decreased by 6.7 percent (p<0.001). The rate of in-hospital mortality, APR and 30-day readmission was 1.3%, 16.3%, and 7.2%, respectively, and the median LOS was 13 days. The adjusted risk of in-hospital mortality (OR = 1.49, 95% CI = 1.25-1.78), APR (OR 1.10, 95%CI 1.02-1.19), 30-day readmission (OR 1.49, 95%CI 1.38-1.61), and prolonged LOS (OR 2.29, 95%CI 2.05-2.55) were greater for low-volume hospitals than for high-volume hospitals. This study shows an independent impact of HV procedures on all short-term outcome measures, justifying a policy of centralization for rectal cancer surgery, a process which is underwa

Metabolic Syndrome and All-Cause and Cardiovascular Mortality in an Italian Elderly Population: The Progetto Veneto Anziani (Pro.V.A.) Study

OBJECTIVE—The purpose of this study was to explore the association of metabolic syndrome and each of its components with all-cause and cardiovascular mortality in a general Italian elderly population

Multimorbidity and Hospital Admissions in High-Need, High-Cost Elderly Patients

Objective: The aim was to clarify which pairs or clusters of diseases predict the hospital-related events and death in a population of patients with complex health care needs (PCHCN). Method: Subjects classified in 2012 as PCHCN in a local health unit by ACG\uae (Adjusted Clinical Groups) System were linked with hospital discharge records in 2013 to identify those who experienced any of a series of hospital admission events and death. Number of comorbidities, comorbidities dyads, and latent classes were used as exposure variable. Regression analyses were applied to examine the associations between dependent and exposure variables. Results: Besides the fact that larger number of chronic conditions is associated with higher odds of hospital admission or death, we showed that certain dyads and classes of diseases have a particularly strong association with these outcomes. Discussion: Unlike morbidity counts, analyzing morbidity clusters and dyads reveals which combinations of morbidities are associated with the highest hospitalization rates or death

Mortality from infectious diseases in diabetes

Background and Aims: to investigate the risk of mortality from infections by comparing the 33 underlying causes of death versus the multiple causes of death in known diabetic subjects living in 34 the Veneto Region, Northern Italy. 35 Methods and Results: 185,341 diabetic subjects aged 30-89 years were identified in the year 2010 36 and causes of death were assessed from 2010 to 2015. Standardized Mortality Ratios (SMR) with 37 95% confidence intervals were computed with regional mortality rates as reference. The underlying 38 causes of death and all the diseases reported in the death certificates were scrutinized. At the end of 39 the follow-up, 36,382 subjects had deceased. We observed an increased risk of death from 40 infection-related causes in subjects affected by diabetes with a SMR of 1.83 (95 % CI, 1.71-1.94). 41 The SMR for death from septicemia was 1.91 (95 % CI, 1.76-2.06) and from pneumonia 1.47 (95 % 42 CI, 1.36-1.59). The use of the multiple causes of death approach emphasized the contribution of 43 infectious diseases to mortality. 44 CONCLUSION: the results of the present study demonstrate an excess mortality from infection45 related diseases in patients affected by diabetes and, more interestingly, show a possible 46 underestimation of the impact of these conditions by routine mortality analyses

PRAME Expression in Mucosal Melanoma of the Head and Neck Region

PRAME (PReferentially expressed Antigen in MElanoma), a cancer-testis antigen expressed in normal and neoplastic tissues with several functions, proved to be a useful diagnostic tool in the differential diagnosis between benign and malignant melanocytic lesions. The current study aims to perform PRAME stain on a retrospective case series of mucosal melanocytic tumors of the head and neck region to compare 3 different scores and evaluate the most reliable one in this diagnostic set. Immunohistochemical analysis for PRAME was performed in 54 benign and malignant mucosal melanocytic tumors of the head and neck region collected from 41 patients. The best-performing cutoff of PRAME-positive cells (nuclear stain) to differentiate benign and malignant mucosal melanocytic tumors of the head and neck region is that proposed by Raghavan and colleagues (&lt;60%/≥60% of PRAME-positive cells), with 100% and 77.8% of benign lesions and malignant tumors respectively correctly identified. Applying this score, PRAME stain showed the best results (sensitivity, specificity, accuracy, and positive and negative predictive values) for the diagnosis of head and neck melanocytic tumors. However, a subset of PRAME-negative malignant tumors was identified, especially located in the palatal area (hard and soft palate). Finally, high PRAME expression (≥60%) was associated with specific sites (nasal cavity/nasal septum/turbinates nasopharynx, and the maxillary sinus), nodular histotype, and female sex

Clinical Impact of Pretransplant Multidrug-Resistant Gram-Negative Colonization in Autologous and Allogeneic Hematopoietic Stem Cell Transplantation

Abstract Multidrug-resistant Gram-negative bacteria (MDR-GNB) are an emerging cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Three-hundred forty-eight consecutive patients transplanted at our hospital from July 2012 to January 2016 were screened for a pretransplant MDR-GNB colonization and evaluated for clinical outcomes. A pretransplant MDR-GNB colonization was found in 16.9% of allo-HSCT and in 9.6% of auto-HSCT recipients. Both in auto- and in allo-HSCT, carriers of a MDR-GNB showed no significant differences in overall survival (OS), transplant-related mortality (TRM), or infection-related mortality (IRM) compared with noncarriers. OS at 2 years for carriers compared with noncarriers was 85% versus 81% ( P  = .262) in auto-HSCT and 50% versus 43% ( P  = .091) in allo-HSCT. TRM at 2 years was 14% versus 5% ( P  = .405) in auto-HSCT and 31% versus 25% ( P  = .301) in allo-HSCT. IRM at 2 years was 14% versus 2% ( P  = .142) in auto-HSCT and 23% versus 14% ( P  = .304) in allo-HSCT. In multivariate analysis, only grade III to IV acute graft-versus-host disease was an independent factor for reduced OS ( P P P P  = .207). We conclude that in this extended single-center experience, a pretransplant MDR-GNB colonization did not significantly influence OS, TRM, and IRM both in auto- and allo-HSCT settings and that MDR-GNB attributed mortality can be controlled in carriers when an early pre-emptive antimicrobial therapy is started in case of neutropenic fever

Infections after Allogenic Transplant with Post-Transplant Cyclophosphamide: Impact of Donor HLA Matching

ABSTRACT Incidence and outcome of infections after allogeneic hematopoietic stem cell transplantation (HSCT) with post-transplant cyclophosphamide (PT-Cy) as graft-versus-host disease (GVHD) prophylaxis are largely unknown. Study aims were to estimate the incidence of pre-engraftment bloodstream infections (PE-BSIs) and viral infections (VIs; cytomegalovirus [CMV], adenovirus [ADV], human herpes virus 6 [HHV6], and BK-polyomavirus hemorrhagic-cystitis [BKPyV-HC]), their predictive factors, and infection-related mortality (IRM) after HSCT with PT-Cy. We analyzed 235 patients: 62%, 21%, and 17% received haploidentical (haplo), matched-unrelated donor (MUD), and matched-related donor, respectively. Overall, 72 patients had 77 PE-BSI episodes at a median time of 13 days after HSCT: cumulative incidence function (CIF) at 28 days was 32%, without differences among donor types (P = .988). By multivariate analysis, CIF of PE-BSI was higher in patients with severe neutropenia before HSCT (adjusted hazard ratio [AHR] = 2.90) and in multidrug-resistant Gram-negative bacteria rectal carriers (AHR = 2.68). IRM at 30 days was 5%, without differences by donor type (P = .106). Overall, 208 patients experienced ≥1 VIs (first occurrence among CMV, HHV6, ADV, BKPyV-HC) at a median time of 20 days after HSCT: CIF at 90 days was 91%, significantly higher in MUD and haplo (P = .0089). By multivariate analysis, also acute GVHD grade ≥2 (AHR = 1.32) and host/donor CMV-serology mismatch (positive/positive versus negative/negative: AHR = 2.95, positive/negative versus negative/negative: AHR = 2.41, negative/positive versus negative/negative: AHR = 2.35) affected VIs occurrence. IRM at 180 days was 8%, without differences among donor types (P = .106). In conclusion, study results did not show a significant impact of donor type on PE-BSI incidence; conversely, MUD and haploidentical transplants retained a higher occurrence of VIs in the early phase after HSCT