Showing papers by "Catholic University of the Sacred Heart published in 2018"

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

International Expert Consensus Document on Takotsubo Syndrome (Part I): Clinical Characteristics, Diagnostic Criteria, and Pathophysiology

Abstract: Takotsubo syndrome (TTS) is a poorly recognized heart disease that was initially regarded as a benign condition. Recently, it has been shown that TTS may be associated with severe clinical complications including death and that its prevalence is probably underestimated. Since current guidelines on TTS are lacking, it appears timely and important to provide an expert consensus statement on TTS. The clinical expert consensus document part I summarizes the current state of knowledge on clinical presentation and characteristics of TTS and agrees on controversies surrounding TTS such as nomenclature, different TTS types, role of coronary artery disease, and etiology. This consensus also proposes new diagnostic criteria based on current knowledge to improve diagnostic accuracy.

Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy

Abstract: Background Nusinersen is an antisense oligonucleotide drug that modulates pre–messenger RNA splicing of the survival motor neuron 2 (SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA). Methods We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale–Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (≥3 points), an outcome that indicates impro...

Hyperprogressive Disease in Patients With Advanced Non-Small Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or With Single-Agent Chemotherapy

Abstract: Importance Hyperprogressive disease (HPD) is a new pattern of progression recently described in patients with cancer treated with programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors. The rate and outcome of HPD in advanced non–small cell lung cancer (NSCLC) are unknown. Objectives To investigate whether HPD is observed in patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors compared with single-agent chemotherapy and whether there is an association between treatment and HPD. Design, Setting, and Participants In this multicenter retrospective study that included patients treated between August 4, 2011, and April 5, 2017, the setting was pretreated patients with advanced NSCLC who received PD-1/PD-L1 inhibitors (8 institutions) or single-agent chemotherapy (4 institutions) in France. Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) on at least 2 computed tomographic scans before treatment and 1 computed tomographic scan during treatment was required. Interventions The tumor growth rate (TGR) before and during treatment and variation per month (ΔTGR) were calculated. Hyperprogressive disease was defined as disease progression at the first evaluation with ΔTGR exceeding 50%. Main Outcomes and Measures The primary end point was assessment of the HPD rate in patients treated with IO or chemotherapy. Results Among 406 eligible patients treated with PD-1/PD-L1 inhibitors (63.8% male), 46.3% (n = 188) were 65 years or older, 72.4% (n = 294) had nonsquamous histology, and 92.9% (n = 377) received a PD-1 inhibitor as monotherapy in second-line therapy or later. The median follow-up was 12.1 months (95% CI, 10.1-13.8 months), and the median overall survival (OS) was 13.4 months (95% CI, 10.2-17.0 months). Fifty-six patients (13.8%) were classified as having HPD. Pseudoprogression was observed in 4.7% (n = 19) of the population. Hyperprogressive disease was significantly associated with more than 2 metastatic sites before PD-1/PD-L1 inhibitors compared with non-HPD (62.5% [35 of 56] vs 42.6% [149 of 350];P = .006). Patients experiencing HPD within the first 6 weeks of PD-1/PD-L1 inhibitor treatment had significantly lower OS compared with patients with progressive disease (median OS, 3.4 months [95% CI, 2.8-7.5 months] vs 6.2 months [95% CI, 5.3-7.9 months]; hazard ratio, 2.18 [95% CI, 1.29-3.69];P = .003). Among 59 eligible patients treated with chemotherapy, 3 (5.1%) were classified as having HPD. Conclusions and Relevance Our study suggests that HPD is more common with PD-1/PD-L1 inhibitors compared with chemotherapy in pretreated patients with NSCLC and is also associated with high metastatic burden and poor prognosis in patients treated with PD-1/PD-L1 inhibitors. Additional studies are needed to determine the molecular mechanisms involved in HPD.

The Past, Present, and Future of Virtual and Augmented Reality Research: A Network and Cluster Analysis of the Literature

Abstract: The recent appearance of low cost Virtual Reality (VR) technologies – like the Oculus Rift, the HTC Vive and the Sony PlayStation VR – and Mixed Reality Interfaces (MRITF) – like the Hololens – is attracting the attention of users and researchers suggesting it may be the next largest stepping stone in technological innovation. However, the history of VR technology is longer than it may seem: the concept of VR was formulated in the 1960s and the first commercial VR tools appeared in the late 1980s. For this reason, during the last twentyyears, hundreds of researchers explored the processes, effects and applications of this technology producing thousands of scientific papers. What is the outcome of this significant research work? This paper wants to provide an answer to this question by exploring, using advanced scientometric techniques, the existing research corpus in the field. We collected all the existent articles about VR in the Web of Science Core Collection scientific database, and the resultant dataset contained 21,667 records for VR and 9,944 for AR. The bibliographic record contained various fields, such as author, title, abstract, country, and all the references (needed for the citation analysis). The network and cluster analysis of the literature showed a composite panorama characterized by evolutions over the time. Indeed, whether until five years ago, the main publication media on VR concerned both conference proceeding and journals, more recently journals constitute the main medium. Similarly, if at first computer science was the leading research field, nowadays clinical areas increased, as well as the number of countries involved in virtual reality research. The present work discusses the evolution of the use of virtual reality in the main areas of application with an emphasis on the future expected virtual reality’s capacities, increases and challenges. We conclude considering the disruptive contribution that VR/AR/MRITF will be able to get in scientific fields, as well in human communication and interaction, as already happened with the advent of mobile phones by increasing the use and the development of scientific applications (e.g. in clinical areas) and by modifying the social communication and interaction among people.

International Expert Consensus Document on Takotsubo Syndrome (Part II): Diagnostic Workup, Outcome, and Management

Abstract: The clinical expert consensus statement on takotsubo syndrome (TTS) part II focuses on the diagnostic workup, outcome, and management. The recommendations are based on interpretation of the limited clinical trial data currently available and experience of international TTS experts. It summarizes the diagnostic approach, which may facilitate correct and timely diagnosis. Furthermore, the document covers areas where controversies still exist in risk stratification and management of TTS. Based on available data the document provides recommendations on optimal care of such patients for practising physicians.

Pitfalls in the measurement of muscle mass: a need for a reference standard

Abstract: BACKGROUND: All proposed definitions of sarcopenia include the measurement of muscle mass, but the techniques and threshold values used vary. Indeed, the literature does not establish consensus on the best technique for measuring lean body mass. Thus, the objective measurement of sarcopenia is hampered by limitations intrinsic to assessment tools. The aim of this study was to review the methods to assess muscle mass and to reach consensus on the development of a reference standard. METHODS: Literature reviews were performed by members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis working group on frailty and sarcopenia. Face-to-face meetings were organized for the whole group to make amendments and discuss further recommendations. RESULTS: A wide range of techniques can be used to assess muscle mass. Cost, availability, and ease of use can determine whether the techniques are better suited to clinical practice or are more useful for research. No one technique subserves all requirements but dual energy X-ray absorptiometry could be considered as a reference standard (but not a gold standard) for measuring muscle lean body mass. CONCLUSIONS: Based on the feasibility, accuracy, safety, and low cost, dual energy X-ray absorptiometry can be considered as the reference standard for measuring muscle mass.

Phenolic Profile and Susceptibility to Fusarium Infection of Pigmented Maize Cultivars.

Abstract: Maize is a staple food source in the world, whose ancient varieties or landraces are receiving a growing attention. In this work, two Italian maize cultivars with pigmented kernels and one inbred line were investigated for untargeted phenolic profile, in vitro antioxidant capacity and resistance to Fusarium verticillioides infection. “Rostrato Rosso” was the richest in anthocyanins whilst phenolic acids were the second class in abundance, with comparable values detected between cultivars. Tyrosol equivalents were also the highest in “Rostrato Rosso” (822.4 mg kg-1). Coherently, “Rostrato Rosso” was highly resistant to fungal penetration and diffusion. These preliminary finding might help in breeding programs, aiming to develop maize lines being more resistant to infections and with improved nutraceutical value.

Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database

Abstract: Background Most patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival Objective and design This observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age Results 3119 patients were followed for a total of 24 475 years Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively Ovarian cancer occurred mainly premenopausally By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0% Path_PMS2 carriers had lower risk for cancer Conclusion Carriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient's age, gender and path_MMR variant We have updated our open-access website wwwlscariskorg to facilitate this

The Enhancement of Plant Disease Resistance Using CRISPR/Cas9 Technology.

Abstract: Genome editing technologies have progressed rapidly and become one of the most important genetic tools in the implementation of pathogen resistance in plants. Recent years have witnessed the emergence of site directed modification methods using meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindrome repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). Recently, CRISPR/Cas9 has largely overtaken the other genome editing technologies due to the fact that it is easier to design and implement, has a higher success rate, and is more versatile and less expensive. This review focuses on the recent advances in plant protection using CRISPR/Cas9 technology in model plants and crops in response to viral, fungal and bacterial diseases. As regards the achievement of viral disease resistance, the main strategies employed in model species such as Arabidopsis and Nicotiana benthamiana, which include the integration of CRISPR-encoding sequences that target and interfere with the viral genome and the induction of a CRISPR-mediated targeted mutation in the host plant genome, will be discussed. Furthermore, as regards fungal and bacterial disease resistance, the strategies based on CRISPR/Cas9 targeted modification of susceptibility genes in crop species such as rice, tomato, wheat, and citrus will be reviewed. After spending years deciphering and reading genomes, researchers are now editing and rewriting them to develop crop plants resistant to specific pests and pathogens.

Philadelphia chromosome-negative classical myeloproliferative neoplasms: Revised management recommendations from European LeukemiaNet

Abstract: This document updates the recommendations on the management of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs) published in 2011 by the European LeukemiaNet (ELN) consortium. Recommendations were produced by multiple-step formalized procedures of group discussion. A critical appraisal of evidence by using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology was performed in the areas where at least one randomized clinical trial was published. Seven randomized controlled trials provided the evidence base; earlier phase trials also informed recommendation development. Key differences from the 2011 diagnostic recommendations included: lower threshold values for hemoglobin and hematocrit and bone marrow examination for diagnosis of polycythemia vera (PV), according to the revised WHO criteria; the search for complementary clonal markers, such as ASXL1, EZH2, IDH1/IDH2, and SRSF2 for the diagnosis of myelofibrosis (MF) in patients who test negative for JAK2V617, CALR or MPL driver mutations. Regarding key differences of therapy recommendations, both recombinant interferon alpha and the JAK1/JAK2 inhibitor ruxolitinib are recommended as second-line therapies for PV patients who are intolerant or have inadequate response to hydroxyurea. Ruxolitinib is recommended as first-line approach for MF-associated splenomegaly in patients with intermediate-2 or high-risk disease; in case of intermediate-1 disease, ruxolitinib is recommended in highly symptomatic splenomegaly. Allogeneic stem cell transplantation is recommended for transplant-eligible MF patients with high or intermediate-2 risk score. Allogeneic stem cell transplantation is also recommended for transplant-eligible MF patients with intermediate-1 risk score who present with either refractory, transfusion-dependent anemia, blasts in peripheral blood > 2%, adverse cytogenetics, or high-risk mutations. In these situations, the transplant procedure should be performed in a controlled setting.

Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes

Abstract: We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

Idiopathic pulmonary fibrosis: pathogenesis and management.

Abstract: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease characterized by the aberrant accumulation of fibrotic tissue in the lungs parenchyma, associated with significant morbidity and poor prognosis. This review will present the substantial advances achieved in the understanding of IPF pathogenesis and in the therapeutic options that can be offered to patients, and will address the issues regarding diagnosis and management that are still open. Over the last two decades much has been clarified about the pathogenic pathways underlying the development and progression of the lung scarring in IPF. Sustained alveolar epithelial micro-injury and activation has been recognised as the trigger of several biological events of disordered repair occurring in genetically susceptible ageing individuals. Despite multidisciplinary team discussion has demonstrated to increase diagnostic accuracy, patients can still remain unclassified when the current diagnostic criteria are strictly applied, requiring the identification of a Usual Interstitial Pattern either on high-resolution computed tomography scan or lung biopsy. Outstanding achievements have been made in the management of these patients, as nintedanib and pirfenidone consistently proved to reduce the rate of progression of the fibrotic process. However, many uncertainties still lie in the correct use of these drugs, ranging from the initial choice of the drug, the appropriate timing for treatment and the benefit-risk ratio of a combined treatment regimen. Several novel compounds are being developed in the perspective of a more targeted therapeutic approach; in the meantime, the supportive care of these patients and their carers should be appropriately prioritized, and greater efforts should be made toward the prompt identification and management of relevant comorbidities. Building on the advances in the understanding of IPF pathobiology, the further investigation of the role of gene variants, epigenetic alterations and other molecular biomarkers reflecting disease activity and behaviour will hopefully enable earlier and more confident diagnosis, improve disease phenotyping and support the development of novel agents for personalized treatment of IPF.

Tropospheric Ozone Assessment Report: Present-day tropospheric ozone distribution and trends relevant to vegetation

Abstract: This Tropospheric Ozone Assessment Report (TOAR) on the current state of knowledge of ozone metrics of relevance to vegetation (TOAR-Vegetation) reports on present-day global distribution of ozone at over 3300 vegetated sites and the long-term trends at nearly 1200 sites. TOAR-Vegetation focusses on three metrics over vegetation-relevant time-periods across major world climatic zones: M12, the mean ozone during 08:00–19:59; AOT40, the accumulation of hourly mean ozone values over 40 ppb during daylight hours, and W126 with stronger weighting to higher hourly mean values, accumulated during 08:00–19:59. Although the density of measurement stations is highly variable across regions, in general, the highest ozone values (mean, 2010–14) are in mid-latitudes of the northern hemisphere, including southern USA, the Mediterranean basin, northern India, north, north-west and east China, the Republic of Korea and Japan. The lowest metric values reported are in Australia, New Zealand, southern parts of South America and some northern parts of Europe, Canada and the USA. Regional-scale assessments showed, for example, significantly higher AOT40 and W126 values in East Asia (EAS) than Europe (EUR) in wheat growing areas (p TOAR-Vegetation provides recommendations to facilitate a more complete global assessment of ozone impacts on vegetation in the future, including: an increase in monitoring of ozone and collation of field evidence of the damaging effects on vegetation; an investigation of the effects on peri-urban agriculture and in mountain/upland areas; inclusion of additional pollutant, meteorological and inlet height data in the TOAR dataset; where not already in existence, establishing new region-specific thresholds for vegetation damage and an innovative integration of observations and modelling including stomatal uptake of the pollutant.

Effect of Targeted Polymyxin B Hemoperfusion on 28-Day Mortality in Patients With Septic Shock and Elevated Endotoxin Level: The EUPHRATES Randomized Clinical Trial.

Abstract: Importance Polymyxin B hemoperfusion reduces blood endotoxin levels in sepsis. Endotoxin activity can be measured in blood with a rapid assay. Treating patients with septic shock and elevated endotoxin activity using polymyxin B hemoperfusion may improve clinical outcomes. Objective To test whether adding polymyxin B hemoperfusion to conventional medical therapy improves survival compared with conventional therapy alone among patients with septic shock and high endotoxin activity. Design, Setting, and Participants Multicenter, randomized clinical trial involving 450 adult critically ill patients with septic shock and an endotoxin activity assay level of 0.60 or higher enrolled between September 2010 and June 2016 at 55 tertiary hospitals in North America. Last follow-up was June 2017. Interventions Two polymyxin B hemoperfusion treatments (90-120 minutes) plus standard therapy completed within 24 hours of enrollment (n = 224 patients) or sham hemoperfusion plus standard therapy (n = 226 patients). Main Outcomes and Measures The primary outcome was mortality at 28 days among all patients randomized (all participants) and among patients randomized with a multiple organ dysfunction score (MODS) of more than 9. Results Among 450 eligible enrolled patients (mean age, 59.8 years; 177 [39.3%] women; mean APACHE II score 29.4 [range, 0-71 with higher scores indicating greater severity), 449 (99.8%) completed the study. Polymyxin B hemoperfusion was not associated with a significant difference in mortality at 28 days among all participants (treatment group, 84 of 223 [37.7%] vs sham group 78 of 226 [34.5%]; risk difference [RD], 3.2%; 95% CI, −5.7% to 12.0%; relative risk [RR], 1.09; 95% CI, 0.85-1.39; P = .49) or in the population with a MODS of more than 9 (treatment group, 65 of 146 [44.5%] vs sham, 65 of 148 [43.9%]; RD, 0.6%; 95% CI, −10.8% to 11.9%; RR, 1.01; 95% CI, 0.78-1.31; P = .92). Overall, 264 serious adverse events were reported (65.1% treatment group vs 57.3% sham group). The most frequent serious adverse events were worsening of sepsis (10.8% treatment group vs 9.1% sham group) and worsening of septic shock (6.6% treatment group vs 7.7% sham group). Conclusions and Relevance Among patients with septic shock and high endotoxin activity, polymyxin B hemoperfusion treatment plus conventional medical therapy compared with sham treatment plus conventional medical therapy did not reduce mortality at 28 days. Trial Registration ClinicalTrials.gov Identifier:NCT01046669

Gut microbiota and aging.

Abstract: The hypothesis of an important role of gut microbiota in maintaining physiological state into the gastrointestinal (GI) system is supported by qualitative and quantitative alteration of the intestinal flora in a number of physiological and pathological condition as shown in several studies. The evidence of the inflammatory state alteration, highlighted in neurodegenerative diseases such as Parkinson's and Alzheimer's strongly recalls the microbiota disturbance, highly suggesting a link between the gastrointestinal system and cognitive functions. Given this perspective, looking at the mutual influence between microbiota products, inflammation mediators and immune system, the modulation of gut microbiota may help to facilitate a physiological and non-pathological aging process and, perhaps, to contrast the progression of degenerating mechanisms. Some studies have already characterized gut microbiota in elderly, with promising results. Future studies should be designed to better understand the correlation between the gut microbiota, the ageing process and degenerative diseases typical of the elderly.

Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.

Abstract: C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10−8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome.

Abstract: Background: Implicit in the genetic evaluation of patients with suspected genetic diseases is the assumption that the genes evaluated are causative for the disease based on robust scientific and st...

Tropospheric ozone assessment report: Global ozone metrics for climate change, human health, and crop/ecosystem research

Abstract: Assessment of spatial and temporal variation in the impacts of ozone on human health, vegetation, and climate requires appropriate metrics. A key component of the Tropospheric Ozone Assessment Report (TOAR) is the consistent calculation of these metrics at thousands of monitoring sites globally. Investigating temporal trends in these metrics required that the same statistical methods be applied across these ozone monitoring sites. The nonparametric Mann-Kendall test (for significant trends) and the Theil-Sen estimator (for estimating the magnitude of trend) were selected to provide robust methods across all sites. This paper provides the scientific underpinnings necessary to better understand the implications of and rationale for selecting a specific TOAR metric for assessing spatial and temporal variation in ozone for a particular impact. The rationale and underlying research evidence that influence the derivation of specific metrics are given. The form of 25 metrics (4 for model-measurement comparison, 5 for characterization of ozone in the free troposphere, 11 for human health impacts, and 5 for vegetation impacts) are described. Finally, this study categorizes health and vegetation exposure metrics based on the extent to which they are determined only by the highest hourly ozone levels, or by a wider range of values. The magnitude of the metrics is influenced by both the distribution of hourly average ozone concentrations at a site location, and the extent to which a particular metric is determined by relatively low, moderate, and high hourly ozone levels. Hence, for the same ozone time series, changes in the distribution of ozone concentrations can result in different changes in the magnitude and direction of trends for different metrics. Thus, dissimilar conclusions about the effect of changes in the drivers of ozone variability (e.g., precursor emissions) on health and vegetation exposure can result from the selection of different metrics.

Impact of Maternal Age on Oocyte and Embryo Competence

Abstract: The overall success of human reproduction, either spontaneously or after IVF, is highly dependent upon maternal age. The main reasons for age-related infertility include reduced ovarian reserve and decreased oocyte/embryo competence due to aging insults, especially concerning an increased incidence of aneuploidies and possibly decreased mitochondrial activity. Age-related chromosomal abnormalities mainly arise because of meiotic impairments during oogenesis, following flawed chromosome segregation patterns such as non-disjunction, premature separation of sister chromatids, or the recent reverse segregation. In this review, we briefly discuss the main mechanisms putatively impaired by aging in the oocytes and the deriving embryos. We also report the main strategies proposed to improve the management of advanced maternal age women in IVF: fertility preservation through oocyte cryopreservation to prevent aging; optimization of the ovarian stimulation and enhancement of embryo selection to limit its effects; and oocyte donation to circumvent its consequences.