439 research outputs found

    Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer.

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    Background: AKT pathway activation is implicated in endocrine-therapy resistance. Data on the efficacy and safety of the AKT inhibitor capivasertib, as an addition to fulvestrant therapy, in patients with hormone receptor-positive advanced breast cancer are limited. Methods: In a phase 3, randomized, double-blind trial, we enrolled eligible pre-, peri-, and postmenopausal women and men with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer who had had a relapse or disease progression during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy. Patients were randomly assigned in a 1:1 ratio to receive capivasertib plus fulvestrant or placebo plus fulvestrant. The dual primary end point was investigator-assessed progression-free survival assessed both in the overall population and among patients with AKT pathway-altered (PIK3CA, AKT1, or PTEN) tumors. Safety was assessed. Results: Overall, 708 patients underwent randomization; 289 patients (40.8%) had AKT pathway alterations, and 489 (69.1%) had received a CDK4/6 inhibitor previously for advanced breast cancer. In the overall population, the median progression-free survival was 7.2 months in the capivasertib-fulvestrant group, as compared with 3.6 months in the placebo-fulvestrant group (hazard ratio for progression or death, 0.60; 95% confidence interval [CI], 0.51 to 0.71; P<0.001). In the AKT pathway-altered population, the median progression-free survival was 7.3 months in the capivasertib-fulvestrant group, as compared with 3.1 months in the placebo-fulvestrant group (hazard ratio, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The most frequent adverse events of grade 3 or higher in patients receiving capivasertib-fulvestrant were rash (in 12.1% of patients, vs. in 0.3% of those receiving placebo-fulvestrant) and diarrhea (in 9.3% vs. 0.3%). Adverse events leading to discontinuation were reported in 13.0% of the patients receiving capivasertib and in 2.3% of those receiving placebo. Conclusions: Capivasertib-fulvestrant therapy resulted in significantly longer progression-free survival than treatment with fulvestrant alone among patients with hormone receptor-positive advanced breast cancer whose disease had progressed during or after previous aromatase inhibitor therapy with or without a CDK4/6 inhibitor. (Funded by AstraZeneca and the National Cancer Institute; CAPItello-291 ClinicalTrials.gov number, NCT04305496.)

    Working in (Slow) Progress: Socio-Environmental and Economic Dynamics in the Forestry Sector and the Contribution to Sustainable Development in Europe

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    Forest ecosystems are increasingly subject to disturbances, such as extreme (climate) events, fires and pathological outbreaks, which exert significant (and still poorly quantified) economic impacts, despite their intrinsic resilience. How forest management addresses these challenges will have profound effects on human health, environmental diversity, (ecological and economic) productivity and the ability of forest ecosystems to recovery from exogenous shocks. Assuming forests as ensuring ecosystem services that are vital to society and human well-being, in addition to providing wood material, a better knowledge of forest ecosystems appears a key requirement to delineate a developmental strategy that guarantees environmental protection objectives and achievement of climate and energy targets. In the context of Sustainable Development Goals of the United Nations 2030 Agenda, the information available on forest management practices in Europe still seems not completely suitable to provide a comprehensive overview of ecosystem conditions, their economic value, and their biodiversity. Based on a literature review, the present contribution focuses on recent dynamics of the forestry sector in Europe, delineating the inherent complexity in the environmental-economic nexus. Additionally, the extensive use of a key natural resource such as wood exerts social implications for local districts adapting to ecological change-from climate warming to landscape transformations. In line with earlier studies, our paper confirms the role of the technical-economic dimension of forestry in sustainable development paths of districts and regions, affecting together (i) short-term economic dynamics, (ii) the growth prospects of the sector, (iii) the organization of the supply chain, (iv) the interconnections between companies, and (v) investment strategies at large. One of the major issues is the low reliability of official statistics to provide a coherent picture of the actual status of forest resources. At the same time, forestry practices are pivotal in maintaining habitats and species while increasing the timber production that remains (too) sustainable. This is the policy direction constantly given by the European Commission to stimulate over time public bodies and private (in whose hands is about 60% of European forests) to start virtuous paths in the circular economy with considerable repercussions in terms of additional jobs, recycled materials, mt of CO2 equivalent avoided, and increase in community added value. In this context, forestry should assure a more 'holistic' contribution to sustainable development paths at various spatial scales. This means concentrating on both economic and environmental targets based on the identification of significant (ecological-economic) dimensions that may delineate future lines of investigation and policy intervention, while increasing between member countries and regional authorities

    IDegLira for the Real-World Treatment of Type 2 Diabetes in Italy: Protocol and Interim Results from the REX Observational Study

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    Introduction: IDegLira was shown to maintain glycemic control while reducing risk of hypoglycemia and body weight gain. The REX study was designed to generate real-world evidence on the use of IDegLira in Italian clinical practice in two different subgroups of patients, those switching to IDegLira from a basal insulin-supported oral therapy (BOT group) and those from a basal plus bolus insulin regimen (BB group). Methods: Adult patients with T2D diagnosed for at least 12 months and having started IDegLira 2–3 months prior to enrolment, coming from a BOT or BB regimen, were enrolled in this multicenter observational prospective cohort study conducted in 28 Italian centers. This paper presents the methodological framework of the REX study and provides the interim analysis results describing the patients’ baseline characteristics and the clinical reasons for IDegLira treatment initiation. Results: Of the 360 patients enrolled in the REX study, 331 were considered eligible for this interim analysis, 76.4% in the BOT and 23.6% in the BB group. Mean (SD) HbA1c was 8.5% (1.4) in the BOT and 8.2% (1.7) in the BB group. The most common T2D complications were diabetic macroangiopathy and diabetic nephropathy in both groups. The median (interquartile range) insulin daily dose before IDegLira was 15.0 (10.0–20.0) units in the BOT group and 42 (30.0–52.0) in the BB group. Oral antidiabetics were taken by 98% and 51.3% of patients, respectively. The main reason for switching to IDegLira was the inadequate glycemic control in the BOT group (86% of patients), and the intent to simplify the treatment in the BB group (66.7%). Conclusions: IdegLira is initiated after BOT in inadequately controlled patients to improve glycemic control, whereas in BB patients it is used to simplify the therapeutic regimen. Final results of the REX study will shed light on patients’ outcomes after IdegLira treatment under routine clinical care

    Nonthyroidal illness syndrome (NTIS) in severe COVID-19 patients: role of T3 on the Na/K pump gene expression and on hydroelectrolytic equilibrium

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    Background: Nonthyroidal Illness Syndrome (NTIS) can be detected in many critical illnesses. Recently, we demonstrated that this condition is frequently observed in COVID-19 patients too and it is correlated with the severity the disease. However, the exact mechanism through which thyroid hormones influence the course of COVID-19, as well as that of many other critical illnesses, is not clear yet and treatment with T4, T3 or a combination of both is still controversial. Aim of this study was to analyze body composition in COVID-19 patients in search of possible correlation with the thyroid function. Methods and findings: We report here our experience performed in 74 critically ill COVID-19 patients hospitalized in the intensive care unit (ICU) of our University Hospital in Rome. In these patients, we evaluated the thyroid hormone function and body composition by Bioelectrical Impedance Analysis (BIA) during the acute phase of the disease at admission in the ICU. To examine the effects of thyroid function on BIA parameters we analyzed also 96 outpatients, affected by thyroid diseases in different functional conditions. We demonstrated that COVID-19 patients with low FT3 serum values exhibited increased values of the Total Body Water/Free Fat Mass (TBW/FFM) ratio. Patients with the lowest FT3 serum values had also the highest level of TBW/FFM ratio. This ratio is an indicator of the fraction of FFM as water and represents one of the best-known body-composition constants in mammals. We found an inverse correlation between FT3 serum values and this constant. Reduced FT3 serum values in COVID-19 patients were correlated with the increase in the total body water (TBW), the extracellular water (ECW) and the sodium/potassium exchangeable ratio (Nae:Ke), and with the reduction of the intracellular water (ICW). No specific correlation was observed in thyroid patients at different functional conditions between any BIA parameters and FT3 serum values, except for the patient with myxedema, that showed a picture similar to that seen in COVID-19 patients with NTIS. Since the Na+/K+ pump is a well-known T3 target, we measured the mRNA expression levels of the two genes coding for the two major isoforms of this pump. We demonstrated that COVID-19 patients with NTIS had lower levels of mRNA of both genes in the peripheral blood mononuclear cells (PBMC)s obtained from our patients during the acute phase of the disease. In addition, we retrieved data from transcriptome analysis, performed on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM)s treated with T3 and we demonstrated that in these cells T3 is able to stimulate the expression of these two genes in a dose-dependent manner. Conclusions: In conclusion, we demonstrated that measurement of BIA parameters is a useful method to analyze water and salt retention in COVID-19 patients hospitalized in ICU and, in particular, in those that develop NTIS. Our results indicate that NTIS has peculiar similarities with myxedema seen in severe hypothyroid patients, albeit it occurs more rapidly. The Na+/K+ pump is a possible target of T3 action, involved in the pathogenesis of the anasarcatic condition observed in our COVID-19 patients with NTIS. Finally, measurement of BIA parameters may represent good endpoints to evaluate the benefit of future clinical interventional trials, based on the administration of T3 in patients with NTIS

    Personalizing Cancer Pain Therapy: Insights from the Rational Use of Analgesics (RUA) Group

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    Introduction: A previous Delphi survey from the Rational Use of Analgesics (RUA) project involving Italian palliative care specialists revealed some discrepancies between current guidelines and clinical practice with a lack of consensus on items regarding the use of strong opioids in treating cancer pain. Those results represented the basis for a new Delphi study addressing a better approach to pain treatment in patients with cancer. Methods: The study consisted of a two-round multidisciplinary Delphi study. Specialists rated their agreement with a set of 17 statements using a 5-point Likert scale (0 = totally disagree and 4 = totally agree). Consensus on a statement was achieved if the median consensus score (MCS) (expressed as value at which at least 50% of participants agreed) was at least 4 and the interquartile range (IQR) was 3–4. Results: This survey included input from 186 palliative care specialists representing all Italian territory. Consensus was reached on seven statements. More than 70% of participants agreed with the use of low dose of strong opioids in moderate pain treatment and valued transdermal route as an effective option when the oral route is not available. There was strong consensus on the importance of knowing opioid pharmacokinetics for therapy personalization and on identifying immediate-release opioids as key for tailoring therapy to patients’ needs. Limited agreement was reached on items regarding breakthrough pain and the management of opioid-induced bowel dysfunction. Conclusion: These findings may assist clinicians in applying clinical evidence to routine care settings and call for a reappraisal of current pain treatment recommendations with the final aim of optimizing the clinical use of strong opioids in patients with cancer

    Drugs Causing Bone Loss

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    Developments in combined analgesic regimens for improved safety in postoperative pain management

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    Introduction: Fixed-dose combination analgesic regimens may be similarly effective to opioid monotherapy but with potentially less risk. A number of individualized combination regimens can be created, including nonopioid agents such as acetaminophen and nonsteroidal anti-inflammatory drugs, opioids, and adjunctive agents such as gabapentin, pregabalin, and muscle relaxants. Areas covered: When such combinations have a synergistic effect, analgesic benefits may be enhanced. Many combination analgesic regimens are opioid sparing, which sometimes but not always results in reduced opioid-associated side effects. Safety concerns for all analgesics must be considered but postoperative analgesia is typically administered for a brief period (days), reducing risks that may occur with prolonged exposure. Expert opinion: Judiciously considered combination analgesic regimens can be effective postoperative analgesics that reduce opioid consumption without compromising pain control, which are important factors for patient recovery and satisfaction. The specific combinations used must be based on the patient, the type and duration of the surgical procedure, and complementary mechanisms of action of the agents used. In opioid-sparing combination analgesic regimens, the short-term use of small doses of opioids in this setting may be helpful for appropriate patients

    A new method to compute the configurational entropy in glassy systems

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    Weight Loss and Eating Pattern 7 Years After Sleeve Gastrectomy. Experience of a Bariatric Center of Excellence

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    Purpose: Report the analysis from a single center series of consecutive primary sleeve gastrectomy (SG) on the factors affecting weight loss at long term. Materials and Methods: Patients submitted to primary SG with a follow-up of 7 years were screened. Weight loss was evaluated with %excess weight loss (%EWL) and %excess BMI loss (%BMIL). Weight regain (WR) was defined as in increase of 25% of the obtained %EWL and insufficient weight loss (IWL) as loss < 50% EWL. Eating behaviors were evaluated with 7 days record (7dR). All the variables potentially affecting the weight loss were cross-matched for correlation. The study population was divided in three groups: group A (WR), group B (IWL), and group C (sustained weight loss) for comparative analysis. Results: A total of 86 patients (21 M/65 F) with a preoperative BMI of 47.08 ± 6.15 kg/m2 were evaluated. Cumulative 7 years weight loss was as follows: 61.66 ± 22.69% EWL and 32 ± 9% EBMIL. A total of 4.6% had an IWL while 27.9% a WR. The analysis showed a significant difference among the daily calories and fats consuming, number of meals, physical activity, grazing/sweet eating habits, and adherence to follow-up (p < 0.05) between groups A and C. Cox hazard demonstrated a significant risk (p < 0.05) to WR in case of adherence to follow-up shorter than 48 months, high daily calories, and fats intake (hazard ratio (HR) range 5–9). Eight patients (9.3%) had a surgical revision. Conclusion: Our data demonstrated that long-term results (7 years) of SG are strongly related to eating habits and patient’s behaviors

    Development Strategies of Agro-Food Sector in Basilicata Region (Italy): Evidence from INNOVAGRO Project

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    Agricultural production in Basilicata Region is strongly characterized by a high degree of fragmentation, the large percentage of small family businesses and a generalized low propensity to entrepreneurship. Although there are productive realities that are suited to entrepreneurship, going beyond the local market dimensions. The low propensity of agricultural producers to associate in consortium or any other formal collaboration is also a factor to be reinforced in order to improve the competitiveness of the respective supply chains. The project “Development of an innovative network for the promotion of extroversion of agro-food companies in Adriatic - Ionian Area” (INNOVAGRO) intents to capitalize existing experiences and to adopt innovative solutions in order to develop an intraregional approach combining innovative ICT technologies, the establishment of a Transnational Innovative Agro-food Network and the promotion of environmentally- friendly farming practices. This work illustrates a detailed context analysis aimed at addressing the general issues promoted by the INNOVAGRO project on specific features characterizing Basilicata Region in supporting new development strategies based on synergic relationships between the tourism sector and agro-food production
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