R&D Policy and Schumpeterian Growth: Theory and Evidence

In recent years, a large body of empirical research has investigated whether the predictions of secondgeneration growth models are consistent with actual data. This strand of literature has focused on the longrun properties of these models by using productivity and innovation data but has not directly assessed the effectiveness of R&D policy in promoting innovation and economic growth. In the present paper, we fill this gap in the literature by providing a unified growth setting that is empirically tested with US manufacturing industry data. Our analysis shows that R&D policy has a persistent, if not permanent, impact on the rate of economic growth and that the economy rapidly adjusts to policy changes. The impact of R&D tax credits on economic growth appears to be long lasting and statistically robust. Conversely, more generous R&D subsidies are associated with an increase in the rate of economic growth in the short run only, indicating that, at best, this policy instrument has only temporary effects. Overall, the evidence regarding the effectiveness of R&D policy provides more support for fully endogenous growth theory than for semi-endogenous growth theory

Low expression of Ki-67/MIB-1 labeling index in IDH wild type glioblastoma predicts prolonged survival independently by MGMT methylation status

PurposeThe Ki-67/MIB-1 labeling index (LI) is clinically used to differentiate between high and low-grade gliomas, while its prognostic value remains questionable. Glioblastoma (GBM) expressing wild-type isocitrate dehydrogenase IDHwt, a relatively common malignant brain tumor in adults, is characterized by a dismal prognosis. Herein, we have retrospectively investigated the prognostic role of Ki-67/MIB-1-LI in a large group of IDHwt GBM.MethodsOne hundred nineteen IDHwt GBM patients treated with surgery followed by Stupp's protocol in our Institution between January 2016 and December 2021 were selected. A cut-off value for Ki-67/MIB-1-LI was used with minimal p-value based approach.ResultsA multivariate analysis showed that Ki-67/MIB-1-LI expression < 15% significantly correlated with a longer overall survival (OS), independently from the age of the patients, Karnofsky performance status scale, extent of surgery and O-6-methylguanine (O6-MeG)-DNA methyltransferase promoter methylation status.ConclusionsAmong other studies focused on Ki-67/MIB-1-LI, this is the first observational study showing a positive correlation between OS of IDHwt GBM patients and Ki-67/MIB-1-LI that we propose as a new predictive marker in this subtype of GBM

Extracellular Vesicles in Pulmonary Hypertension: A Dangerous Liaison?

The term pulmonary hypertension (PH) refers to different conditions, all characterized by increased pressure and resistance in the pulmonary arterial bed. PH has a wide range of causes (essentially, cardiovascular, pulmonary, or connective tissue disorders); however, idiopathic (i.e., without a clear cause) PH exists. This chronic, progressive, and sometimes devastating disease can finally lead to right heart failure and eventually death, through pulmonary vascular remodeling and dysfunction. The exact nature of PH pathophysiology is sometimes still unclear. Extracellular vesicles (EVs), previously known as apoptotic bodies, microvesicles, and exosomes, are small membrane-bound vesicles that are generated by almost all cell types and can be detected in a variety of physiological fluids. EVs are involved in intercellular communication, thus influencing immunological response, inflammation, embryogenesis, aging, and regenerative processes. Indeed, they transport chemokines, cytokines, lipids, RNA and miRNA, and other biologically active molecules. Although the precise functions of EVs are still not fully known, there is mounting evidence that they can play a significant role in the pathophysiology of PH. In this review, after briefly recapping the key stages of PH pathogenesis, we discuss the current evidence on the functions of EVs both as PH biomarkers and potential participants in the distinct pathways of disease progression

Diferencias relacionadas con el sexo en pacientes con IAMCEST: análisis por puntuación de propensión

Supplementary data associated with this article can be found in the online version available at https://doi.org/ 10.24875/RECICE.M19000061.[EN] Introduction and objectives: Female sex is believed to be a significant risk factor for mortality among patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary interventions (pPCI). Methods: We collected data on all consecutive STEMI patients treated with pPCI within 12 hours and compared the males vs the females. The primary endpoint was long-term mortality one month after hospital discharge. The secondary endpoint was 30-days mortality. Results: From March 2006 to December 2016, 1981 patients underwent pPCI at our hospital, 484 (24.4%) were females. Compared with men, women were older (mean age 71.3 ± 11.6 vs 62.9 ± 11.8 years, P < .001), less smokers (26.7% vs 72.7%; P < .001), more diabetic (28.0% vs 22.3%; P < .002), more hypertensive (69.6% vs 61.3%; P < .001), presented more often with shock at baseline (13.2% vs 9.0%; P = .006), had longer symptoms-to-balloon time frames (5.36 ± 3.97 vs 4.47 ± 3.67 hours; P < .001). Also, women were less likely to receive glycoprotein IIb-IIIa inhibitors (59.5% vs 71.4%; P < .001) and stents (79.5% vs 86.6%; P = .01). During the 30-day and long-term follow-up (mean 4.9 ± 3.2 years) the female sex was associated with a higher mortality rate (8.9% vs 4.0%, P < .001 and 23.8% vs 18.4%, P = .01, respectively). After propensity score matching, 379 men and 379 women were selected. Female sex continued to be associated with a higher death rate at 30 days (9.5% vs 5.5%; P = .039) but not in the long term among survivors (25.6% vs 21.4%; P = .170). Conclusions: Compared to men, women with STEMI undergoing pPCI had higher 30-day mortality rates. However, among survivors, the long-term mortality rate was similar. Even if residual confounding cannot be ruled out, this difference in the outcomes may be partially explained by biological sex-related differences.[ES]Introducción y objetivos: El sexo femenino se considera un importante factor de riesgo de mortalidad en el infarto agudo de miocardio con elevación del segmento ST (IAMCEST) tratado con intervención coronaria percutánea primaria (ICPp). Métodos: Se analizó a todos los pacientes consecutivos con IAMCEST tratados con ICPp dentro de las primeras 12 horas, y se compararon varones y mujeres. El objetivo principal fue la mortalidad a largo plazo en los supervivientes después del primer mes del alta, y el objetivo secundario fue la mortalidad a los 30 días. Resultados: Desde marzo de 2006 hasta diciembre de 2016 se trató con ICPp 1.981 a pacientes, de los cuales 484 (24,4%) eran mujeres. En comparación con los varones, las mujeres tenían mayor edad (edad media 71,3 ± 11,6 frente a 62,9 ± 11,8 años, p < 0,001) y la frecuencia de fumadoras era más baja (26,7 frente a 72,7%; p < 0,001), mientras que era más alta la frecuencia de diabetes (28,0 frente a 22,3%; p < 0,002), hipertensión arterial (69.6 frente a 61,3%, p < 0,001) y shock al ingreso (13,2 frente a 9,0%; p = 0,006), y más largo el tiempo desde el comienzo de los síntomas hasta la intervención con balón (5,36 ± 3,97 frente a 4,47 ± 3,67 horas; p < 0,001). Además, la frecuencia de tratamiento con inhibidores de la glucoproteína IIb-IIIa (59,5 frente a 71,4%; p < 0,001) y stent (79,5 frente a 86,6%, p = 0,01) fue inferior. Tanto a los 30 días como a largo plazo (media 4,9 ± 3,2 años), el sexo femenino se asoció con una mortalidad más alta (8,9 frente a 4,0%, p < 0,001, y 23,8 frente a 18,4%, p = 0,01, respectivamente). Se seleccionaron 379 mujeres y 379 varones emparejados por puntuación de propensión. Se mantuvo la asociación entre sexo femenino y mayor mortalidad a los 30 días (9,5 frente a 5,5%; p = 0,039), pero no a largo plazo (25,6 frente a 21,4%; p = 0,170). Conclusiones: En comparación con los varones, las mujeres con IAMCEST tratadas con ICPp tuvieron mayor mortalidad a los 30 días. Sin embargo, entre los supervivientes, la mortalidad a largo plazo fue similar. Aunque no puede descartarse el efecto de variables residuales de confusión, las diferencias en el pronóstico podrían explicarse en parte por diferencias biológicas relacionadas con el sexo.S

CD4 T lymphocyte autophagy is upregulated in the salivary glands of primary Sjögren’s syndrome patients and correlates with focus score and disease activity

Background: Primary Sjögren’s syndrome (pSS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands and peripheral lymphocyte perturbation. In the current study, we aimed to investigate the possible pathogenic implication of autophagy in T lymphocytes in patients with pSS. Methods: Thirty consecutive pSS patients were recruited together with 20 patients affected by sicca syndrome a nd/or chronic sialoadenitis and 30 healthy controls. Disease activity and damage were evaluated according to SS disease activity index, EULAR SS disease activity index, and SS disease damage index. T lymphocytes were analyzed for the expression of autophagy-specific markers by biochemical, molecular, and histological assays in peripheral blood and labial gland biopsies. Serum interleukin (IL)-23 and IL-21 levels were quantified by enzyme-linked immunosorbent assay. Results: Our study provides evidence for the first time that autophagy is upregulated in CD4+ T lymphocyte salivary glands from pSS patients. Furthermore, a statistically significant correlation was detected between lymphocyte autophagy levels, disease activity, and damage indexes. We also found a positive correlation between autophagy enhancement and the increased salivary gland expression of IL-21 and IL-23, providing a further link between innate and adaptive immune responses in pSS. Conclusions: These findings suggest that CD4+ T lymphocyte autophagy could play a key role in pSS pathogenesis. Additionally, our data highlight the potential exploitation of T cell autophagy as a biomarker of disease activity and provide new ground to verify the therapeutic implications of autophagy as an innovative drug target in pSS

The botanical drug PBI-05204, a supercritical CO2 extract of Nerium oleander, sensitizes alveolar and embryonal rhabdomyosarcoma to radiotherapy in vitro and in vivo

: Treatment of rhabdomyosarcoma (RMS), the most common a soft tissue sarcoma in childhood, provides intensive multimodal therapy, with radiotherapy (RT) playing a critical role for local tumor control. However, since RMS efficiently activates mechanisms of resistance to therapies, despite improvements, the prognosis remains still largely unsatisfactory, mainly in RMS expressing chimeric oncoproteins PAX3/PAX7-FOXO1, and fusion-positive (FP)-RMS. Cardiac glycosides (CGs), plant-derived steroid-like compounds with a selective inhibitory activity of the Na+/K+-ATPase pump (NKA), have shown antitumor and radio-sensitizing properties. Herein, the therapeutic properties of PBI-05204, an extract from Nerium oleander containing the CG oleandrin already studied in phase I and II clinical trials for cancer patients, were investigated, in vitro and in vivo, against FN- and FP-RMS cancer models. PBI-05204 induced growth arrest in a concentration dependent manner, with FP-RMS being more sensitive than FN-RMS, by differently regulating cell cycle regulators and commonly upregulating cell cycle inhibitors p21Waf1/Cip1 and p27Cip1/Kip1. Furthermore, PBI-05204 concomitantly induced cell death on both RMS types and senescence in FN-RMS. Notably, PBI-05204 counteracted in vitro migration and invasion abilities and suppressed the formation of spheroids enriched in CD133+ cancer stem cells (CSCs). PBI-05204 sensitized both cell types to RT by improving the ability of RT to induce G2 growth arrest and counteracting the RT-induced activation of both Non-Homologous End-Joining and homologous recombination DSBs repair pathways. Finally, the antitumor and radio-sensitizing proprieties of PBI-05204 were confirmed in vivo. Notably, both in vitro and in vivo evidence confirmed the higher sensitivity to PBI-05204 of FP-RMS. Thus, PBI-05204 represents a valid radio-sensitizing agent for the treatment of RMS, including the intrinsically radio-resistant FP-RMS

STATO DI SALUTE DELLE POPOLAZIONI RESIDENTI NELLE AREE GEOTERMICHE DELLA TOSCANA

Objective The limited scientific knowledge on relationship between exposure and health effects in relation to geothermal activity motivated an epidemiologic investigation in Tuscan geothermal area. The study aims to describe the health status of populations living in Tuscany municipalities where concessions for exploitation of geothermal resources were granted. Design This is an ecological study, so it is not useful to produce evidence to sustain a judgment on the cause-effect link. The major limits of this type of study are the use of the residence at municipal level as a proxy of exposure to both environmental and socioeconomic factors and the use of aggregated data of health outcomes that can lead to the well-known ecological fallacy. Setting and participants Sixteen municipalities were included in the study area: eight are part of the so-called "traditional" geothermal area, defined as Northern Geothermal Area (NGA) and eight located in the Amiata Mountain defined as Southern Geothermal Area (SGA). In 2000-2006, the average resident population in the overall area was approximately 43,000 inhabitants. Thirty-one geothermal power plants were active, with a production capacity of 811 MW, 5 of them with 88 MW located in the SGA. Statistical analyses on the entire geothermal area, NGA and SGA subareas, and the sixteen municipalities were performed. Main outcome measures Mortality data were obtained from Tuscany Regional Mortality Registry for the 1971-2006 period, analysing 60 causes of death, of interest for population health status or consistent with "Project SENTIERI" criteria. Hospital discharge records of residents in Tuscany Region in 2004-2006, anywhere admitted to hospital, were analyzed considering only the main diagnosis, excluding repeated admissions for the same cause. The causes taken into account are the same analysed for mortality were considered. Age-standardized mortality rates (TSDM) and the temporal trends of TSDM for four periods (1971-1979, 1980- 1989, 1990-1999, 2000-2006) were computed. Age-standardized mortality/hospitalization ratios (SMR/SHR), with and without adjustment for the deprivation index based on 2001 census data, were calculated: mortality in the years 2000-2006 and hospitalization in 2004-2006. The expected number of events were computed using rates of residents in neighbouring municipalities (municipalities included in 50 km radius circle centred on the study area). Bayesian estimates of mortality/hospitalization ratios (BMR/BHR) at municipal level only and relating maps of the Bayesian risk estimators were elaborated. Congenital malformations (MC) were analysed using data from Tuscan Registry of Birth Defect in 1992-2006 period, relative to outcomes of pregnancies in women resident in the municipalities of study area, wherever the birth or termination of pregnancy occurred. The ratio between observed and expected cases (O/A), with expected defined according to regional rate, were calculated and O/A Bayesian estimates (BMR) are showed only at municipal level . The low weight and the males/females ratio at birth were analysed using data from Tuscany Birth Certificates, covering period 2001-2007, excluding biths occurred in facilities outside Tuscany Region. For Low birth weight (<2,500 grams), very low birth weight (<1,500 grams), low birth weight in women with normal gestational age or greater than 36 weeks, gestational age less than 36 weeks, and the frequency of males, the observed/expected ratio was calculated, with the expected number defined according to regional rate. Results Environmental background High levels of arsenic in drinking water distribution emerges as a critical element, so that several municipalities resorted to granting exemptions for the parameters laid down by the Legislative Decree in force (DLgs 31/01). However, during the final phase of the study, new blast systems activated in the SGA decreased the arsenic levels in the water supply, reaching values not requiring derogations, which, instead, are still effective in some NGA municipalities. Air quality data, from Tuscany Regional Agency for Environmental Protection-ARPAT, show that geothermal activities are able to affect air quality, especially with hydrogen sulphide in NGA, and hydrogen sulphide and mercury in SGA. A significant contribution to the presence of mercury in air is due to previous metallurgical sites. Although mercury levels are belowWHO guideline values, in SGA nearby Siena, values were significantly higher than in other geothermal areas, because of power plant PC2 (turned off in July 2011) in Piancastagnaio municipality. The hydrogen sulphide concentration levels were generally lower than WHO reference values, with occasional excesses over guideline value for health protection (150 &#956;g/m3 as average of the 24 hours). Olfactory pollution was more critic with values exceeding 7-10 &#956;g/m3 range even in areas without geothermal plants.Obiettivo Le limitate conoscenze scientifiche sui rapporti tra esposizione a fattori ambientali correlati all\u27attivit? geotermica e lo stato di salute della popolazione esposta hanno motivato la conduzione di una indagine epidemiologica nell\u27area geotermica toscana basata sull\u27analisi dei dati ambientali e sanitari disponibili negli archivi regionali. Lo studio ha lo scopo di descrivere lo stato di salute delle popolazioni residenti nelle aree geotermiche toscane, identificate con i territori comunali per i quali sono state rilasciate concessioni di sfruttamento della risorsa geotermica. Disegno Lo studio ? di tipo ecologico e quindi non adatto a produrre evidenze che permettano di esprimere un giudizio sul nesso causa-effetto. I maggiori limiti degli studi ecologici derivano dall\u27assunzione che la residenza anagrafica a livello comunale rappresenti una valida misura di esposizione a fattori sia ambientali sia socioeconomici e dall\u27utilizzo di dati aggregati degli esiti sanitari che possono portare a risultati affetti da fallacia ecologica. Setting e partecipanti I comuni inclusi nell\u27area geotermica dello studio sono 16, di cui 8 compresi nell\u27area geotermica cosiddetta ?tradizionale?, che include le localit? di Larderello, Val di Cornia e Radicondoli-Travale (area geotermica Nord) e gli altri 8 situati nella zona dell\u27Amiata senese e grossetana (area geotemica Sud). Nel periodo 2000-2006 la popolazione media residente nell\u27area geotermica complessiva era di oltre 43.000 abitanti. Al momento dello studio erano attive 31 centrali geotermoelettriche con capacit? di produzione di 811 MW, di cui 5 con 88 MW totali nell\u27area geotermica Sud. Le analisi statistiche sono state effettuate a livello di intera area geotermica, delle due subaree geotermiche (Nord e Sud) e dei 16 comuni. Principali misure di outcome La mortalit? ? stata analizzata utilizzando i dati del Registro di mortalit? regionale della Toscana per l\u27intero periodo disponibile (1971-2006), con dettaglio per 60 cause, scelte in quanto di interesse generale per il profilo di salute della popolazione o perch? coerenti con i criteri adottati dal Progetto SENTIERI. L\u27ospedalizzazione ? stata valutata analizzando i dati delle schede di dimissione ospedaliera (SDO) della Re-gione Toscana nel periodo 2004-2006, includendo i ricoverati residenti in Toscana ovunque abbiano effettuato un ricovero, considerando solo la diagnosi principale di ricovero, escludendo i ricoveri ripetuti degli stessi soggetti per la stessa causa. Le cause di ospedalizzazione selezionate per l\u27analisi dei ricoveri sono le stesse utilizzate per l\u27analisi della mortalit?. Per la mortalit? sono stati calcolati i tassi di mortalit? standardizzati per et? (TSDM) e i trend temporali dei TSDM in quattro periodi (1971- 1979, 1980-1989, 1990-1999, 2000-2006). Sia per la mortalit? del periodo 2000-2006, sia per l\u27ospedalizzazione del periodo 2004-2006,sono stati calcolati: &#61692; i rapporti di mortalit?/ospedalizzazione standardizzati per et? (SMR/SHR), con e senza aggiustamento per l\u27indice di deprivazione (ID), utilizzando per il calcolo dell\u27ID i dati del censimento 2001, con gli attesi calcolati usando il tasso di mortalit?/ospedalizzazione della popolazione residente nei comuni limitrofi (comuni con la coordinata geografica del municipio compresa in un cerchio con raggio di 50 km centrato sull\u27area in studio); &#61692; le stime bayesiane dei rapporti di mortalit? (BMR) e di ospedalizzazione (BHR) a livello esclusivamente comunale; &#61692; le mappe (disease mapping) dei rischi bayesiani di mortalit?/ospedalizzazione comunali. Le malformazioni congenite (MC) sono state analizzate utilizzando i dati del Registro toscano dei difetti congeniti (RTDC) nel periodo 1992-2006, relativi a esiti di gravidanze di donne residenti nei comuni dell\u27area in studio, ovunque sia avvenuto il parto o l\u27interruzione di gravidanza. Per le MC ? stato calcolato il rapporto tra casi osservati e casi attesi (O/A), con gli attesi definiti in base al tasso regionale e vengono fornite le stime bayesiane del rapporto O/A (BMR) a livello esclusivamente comunale. Per valutare il basso peso e il rapporto tra maschi e femmine alla nascita sono stati utilizzati i dati dei certificati di assistenza al parto della Regione Toscana, relativi al periodo 2001-2007, con esclusione degli eventi occorsi in presidi di altre regioni. L\u27analisi ? stata condotta considerando i nati con: basso peso alla nascita (LW: peso <2.500 grammi), bassissimo peso alla nascita (VLW: peso <1.500 grammi), basso peso alla nascita nelle donne con et? gestazionale normale e maggiore di 36 settimane (LW36), et? gestazionale inferiore a 36 settimane, e il numero di maschi osservato. Per tutti gli indicatori ? stato calcolato il rapporto osservato/atteso, con l\u27atteso definito in base al tasso regionale. Risultati Il contesto ambientale Dalla descrizione del contesto ambientale, per quanto riguarda l\u27acqua, emerge come elemento di criticit? il riscontro talvolta di elevati livelli di arsenico nelle acque della rete di distribuzione degli acquedotti, tanto che in diverse realt? comunali si ? dovuto far ricorso alla concessione di deroghe ai parametri previsti dal decreto legislativo vigente (DLgs 31/01). Comunque, durante la fase conclusiva dello studio, nell\u27area geotermica Sud i nuovi sistemi abbattitori hanno ridotto i livelli di arsenico nella rete idrica fino a valori tali da non dover pi? ricorrere alle deroghe, ancora attive, invece, in alcuni comuni dell\u27area geotermica Nord. Le informazioni dell\u27ARPAT sui dati dell\u27aria evidenziano che l\u27attivit? geotermica ? in grado di modificare la qualit? dell\u27aria, soprattutto per l\u27acido solfidrico nell\u27area geotermica Nord, e per l\u27acido solfidrico e il mercurio nell\u27area geotermica Sud, in particolare nel versante senese dell\u27Amiata. Per il mercurio nell\u27aria, un contributo rilevante ? legato anche alle emissioni dagli ex siti metallurgici. Sebbene i livelli di mercurio nelle postazioni di monitoraggio rientrino sempre al di sotto dei valori guida raccomandati dall\u27OMS, le concentrazioni riscontrate nell\u27aria dell\u27Amiata senese, e perlopi? legate alla centrale PC2 di Piancastagnaio (spenta nel luglio 2011), sono significativamente superiori a quelle rilevate nelle altre aree geotermiche che, al contrario, sono assestate sugli stessi livelli registrati nei territori non geotermici. I livelli di concentrazione di acido solfidrico sono inferiori ai valori di riferimento, con occasionali superamenti del valore guida di tutela sanitaria OMS (150 &#956;g/m3 come media delle 24 ore). Pi? critici sono i dati di inquinamento olfattivo, che si verifica con il superamento del valore di 7-10 g/m3 di acido solfidrico nell\u27aria, riscontrato con vario grado di intensit? in tutte le postazioni di monitoraggio, anche in aree dove non sono presenti impianti geotermici. In alcune aree con insediamenti produttivi geotermici la frequenza, la persistenza e l\u27intensit? dei cattivi odori sono tali da comportare condizioni di qualit? dell\u27aria scadente