Performance of the pediatric index of mortality 2 (PIM-2) in cardiac and mixed intensive care units in a tertiary children's referral hospital in Italy

Background: Mortality rate of patients admitted to Intensive Care Units is a widely adopted outcome indicator. Because of large case-mix variability, comparisons of mortality rates must be adjusted for the severity of patient illness at admission. The Pediatric Index of Mortality 2 (PIM-2) has been widely adopted as a tool for adjusting mortality rate by patients' case mix. The objective of this study was to assess the performance of PIM-2 in children admitted to intensive care units after cardiac surgery, other surgery, or for other reasons. Methods: This was a prospective cohort study, conducted in a 607 inpatient-bed tertiary-care pediatric hospital in Italy, with three pediatric intensive care Units (PICUs) and one cardiac Unit (CICU). In 2009-11, all consecutive admissions to PICUs/CICU of children aged 0-16 years were included in the study. Discrimination and calibration measures were computed to assess PIM-2 performance. Multivariable logistic regression analysis was used to assess the association of patients' main reason for intensive care admission (cardiac-surgical, other-surgical, medical), age, Unit and year with observed mortality, adjusting for PIM-2 score. Results: PIM-2 data collection was completed for 91.2% of total PICUs/CICU patient admissions (2912), and for 94.8% of patients who died in PICUs/CICU (129). Overall observed mortality was 4.4% (95% CI, 3.7-5.2), compared to 6.4% (95% CI, 5.5-7.3) expected mortality. Standardised mortality ratio was 0.7 (95% CI: 0.6-0.8). PIM-2 discrimination was fair (area under the curve, 0.79; 95% CI: 0.75-0.83). Calibration was less satisfactory, mainly because of the over two-fold overprediction of deaths in the highest risk group (114.7 vs 53; p < 0.001), and particularly in cardiac-surgical patients. Multivariable logistic analysis showed that risk of death was significantly reduced in cardiac-surgical patients and in those aged 1 month to 12 years, independently from PIM-2. Conclusions: The children age distribution and the proportion of cardiac-surgical patients should be taken into account when interpreting SMRs estimated using the PIM-2 prediction model in different Units. A new calibration study of PIM-2 score might be needed, and more appropriate cardiac-focused risk-adjustment models should be developed. The role of age on risk of death needs to be further explored

CB1 Cannabinoid Receptor is a Target for Neuroprotection in Light Induced Retinal Degeneration

In the last few years, an increasing interest in the neuroprotective effect of cannabinoidshas taken place. The aim of the present work was to study the effects of modulatingcannabinoid receptor 1 (CB1) in the context of light induced retinal degeneration (LIRD),using an animal model that resembles many characteristics of human age-related maculardegeneration (AMD) and other degenerative diseases of the outer retina. Sprague Dawleyrats (n = 28) were intravitreally injected in the right eye with either a CB1 agonist (ACEA), oran antagonist (AM251). Contralateral eyes were injected with respective vehicles ascontrols. Then, rats were subjected to continuous illumination (12,000 lux) for 24 h.Retinas from 28 animals were processed by GFAP-immunohistochemistry (IHC),TUNEL technique, Western blotting (WB), or qRT-PCR. ACEA-treated retinas showeda significantly lower number of apoptotic nuclei in the outer nuclear layer (ONL), lower levelsof activated Caspase-3 by WB, and lower levels of glial reactivity by both GFAP-IHC andWB. qRT-PCR revealed that ACEA significantly decreased the expression of Bcl-2 andCYP1A1. Conversely, AM251-treated retinas showed a higher number of apoptotic nucleiin the ONL, higher levels of activated Caspase-3 by WB, and higher levels of glial reactivityas determined by GFAP-IHC and WB. AM251 increased the expression of Bcl-2, Bad,Bax, Aryl hydrocarbon Receptor (AhR), GFAP, and TNFα. In summary, the stimulation ofthe CB1 receptor, previous to the start of the pathogenic process, improved the survival ofphotoreceptors exposed to LIRD. The modulation of CB1 activity may be used as aneuroprotective strategy in retinal degeneration and deserves further studiesFil: Soliño, Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Larráyoz, Ignacio M.. Center For Biomedical Research Of La Rioja; EspañaFil: Lopez, Ester Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Rey Funes, Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Bareiro, Nidia Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Loidl, Cesar Fabian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Girardi, Elena Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Caltana, Laura Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Brusco, Herminia Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Martinez, Alfredo. Center For Biomedical Research Of La Rioja; EspañaFil: López, Juan José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentin

Parp1 inhibitor and trabectedin combination does not increase tumor mutational burden in advanced sarcomas—a preclinical and translational study

SIMPLE SUMMARY: Immunotherapy has revolutionized cancer treatment, but not for all tumor types. Indeed, sarcomas are considered “immune-cold” tumors, which are relatively unresponsive to immunotherapy. One strategy to potentiate immunotherapy efficacy is to increase tumor immunogenicity, for instance by boosting the number of candidate targets (neoantigens) to be recognized by the immune system. Tumor mutational burden indicates the number of somatic mutations identified in the tumor and normalized per megabase. Tumor mutational burden is considered as an acceptable, measurable surrogate of tumor neoantigens. Here, we explored whether the combination of two DNA-damaging agents, trabectedin and olaparib, could increase tumor mutational burden in sarcomas, to prime subsequent immunotherapy. We found no variation in tumor mutational burden after trabectedin + olaparib in preclinical and clinical samples. Therefore, other aspects should be considered to increase sarcoma immunogenicity, by exploiting different pathways such as the potential modulation of the tumor microenvironment induced by trabectedin + olaparib. ABSTRACT: Drug-induced tumor mutational burden (TMB) may contribute to unleashing the immune response in relatively “immune-cold” tumors, such as sarcomas. We previously showed that PARP1 inhibition perpetuates the DNA damage induced by the chemotherapeutic agent trabectedin in both preclinical models and sarcoma patients. In the present work, we explored acquired genetic changes in DNA repair genes, mutational signatures, and TMB in a translational platform composed of cell lines, xenografts, and tumor samples from patients treated with trabectedin and olaparib combination, compared to cells treated with temozolomide, an alkylating agent that induces hypermutation. Whole-exome and targeted panel sequencing data analyses revealed that three cycles of trabectedin and olaparib combination neither affected the mutational profiles, DNA repair gene status, or copy number alterations, nor increased TMB both in homologous recombinant-defective and proficient cells or in xenografts. Moreover, TMB was not increased in tumor specimens derived from trabectedin- and olaparib-treated patients (5–6 cycles) when compared to pre-treatment biopsies. Conversely, repeated treatments with temozolomide induced a massive TMB increase in the SJSA-1 osteosarcoma model. In conclusion, a trabectedin and olaparib combination did not show mutagenic effects and is unlikely to prime subsequent immune-therapeutic interventions based on TMB increase. On the other hand, these findings are reassuring in the increasing warning of treatment-induced hematologic malignancies correlated to PARP1 inhibitor use

Linking learning with governance in networks and clusters: key issues for analysis and policy

In this paper we analyse the relationship between governance and learning in clusters and networks. In particular, we see these two key elements as interdependent, suggesting that, under particular circumstances, such interdependence may drive clusters and networks towards a dynamic development trajectory. A pure ‘governance perspective’ makes the development of any locality dependent on the system of powers which exists within the locality or across the global value chain. In parallel, a pure ‘competence-based approach’ focuses mainly on the capabilities of actors to learn and undertake activities. In contrast, we open the prospects for an interdependent relation that may change the actual competences of actors as well as the governance settings and dynamics in networks and clusters. When supported by public policies, the learning process may have the potential to modify the governance environment. Simultaneously, the learning process is intrinsically influenced by economic power, which may seriously affect the development prospects of clusters and networks. This is why an intertwined consideration of both aspects is necessary to promote specific approaches to learning and to design appropriate policies. In this paper we offer two preliminary case studies to clarify some of these dynamics: the first taken from the computers cluster in Costa Rica and the second from an Italian bio-pharmaceutical firm and its production network. The first case study refers to the software cluster that was created from scratch in Costa Rica thanks to an enlightened government policy in coordination with new local enterprises and an important foreign direct investor; while the second reflects on the ability of an individual company to create a network of relationships with large transnational companies in order to acquire new competences without falling into a subordinate position with respect to its larger partners

Effect of synbiotic supplementation in children and adolescents with cystic fibrosis: a randomized controlled clinical trial

BACKGROUND/OBJECTIVES:Cystic fibrosis (CF) is characterized by excessive activation of immune processes. The aim of this study was to evaluate the effect of synbiotic supplementation on the inflammatory response in children/adolescents with CF. SUBJECTS/METHODS:A randomized, placebo-controlled, double-blind, clinical-trial was conducted with control group (CG, n = 17), placebo-CF-group (PCFG, n = 19), synbiotic CF-group (SCFG, n = 22), PCFG negative (n = 8) and positive (n = 11) bacteriology, and SCFG negative (n = 12) and positive (n = 10) bacteriology. Markers of lung function (FEV1), nutritional status [body mass index-for age (BMI/A), height-for-age (H/A), weight-for-age (W/A), upper-arm fat area (UFA), upper-arm muscle area (UMA), body fat (%BF)], and inflammation [interleukin (IL)-12, tumor necrosis factor-alpha (TNF-α), IL-10, IL-6, IL-1β, IL-8, myeloperoxidase (MPO), nitric oxide metabolites (NOx)] were evaluated before and after 90-day of supplementation with a synbiotic. RESULTS:No significance difference was found between the baseline and end evaluations of FEV1 and nutricional status markers. A significant interaction (time vs. group) was found for IL-12 (p = 0.010) and myeloperoxidase (p = 0.036) between PCFG and SCFG, however, the difference was not maintained after assessing the groups individually. NOx diminished significantly after supplementation in the SCFG (p = 0.030). In the SCFG with positive bacteriology, reductions were found in IL-6 (p = 0.033) and IL-8 (p = 0.009) after supplementation. CONCLUSIONS: Synbiotic supplementation shown promise at diminishing the pro-inflammatory markers IL-6, IL-8 in the SCFG with positive bacteriology and NOx in the SCFG in children/adolescents with CF

Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer’s disease

Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer’s disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.International Society for Neurochemistry (ISN) and Alexander von Humboldt Foundation (to M.C.D.); Agencia Nacional de Promoción Científica y Tecnológica (PBIT/09 2013, PICT2015-0285 and PICT-2016-4647 to L.M.; PICT-2014-1537 to M.C.D.

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele