Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure <= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.Hospital do Coracao (HCor) as part of the Program 'Hospitais de Excelencia a Servico do SUS (PROADI-SUS)'Brazilian Ministry of Healt

Local knowledge composition and the emergence of entrepreneurial activities across industries: Evidence from Italian NUTS-3 regions

This paper investigates how the characteristics of the local knowledge bases, stemming from the accumulation and recombination of competences over time, spur the emergence of new entrepreneurial activities across industries at the Italian provincial level. To do so, we exploit information on the number of new firms appearing across diverse industries in each Italian NUTS-3 region (province) from 1997 to 2009 as an indicator of local entrepreneurial activity. To build indicators of both local technological knowledge stocks and local technological knowledge compositions, we collect information on patenting activity at the provincial level. Our findings suggest that the availability of local knowledge spillovers is not sufficient per se to trigger the creation of new firms. Indeed, looking at the properties of local knowledge bases, the rate of new firm formation appears to be higher in contexts featured by knowledge stemming from search activities shaped by the accumulated competences and dispersed across a wide area of the technology landscape. This suggests that, in Italy, entrepreneurship is mostly related to the exploitation of technological knowledge accumulated over time rather than to profiting from radical breakthroughs. © 2019, Springer Science+Business Media, LLC, part of Springer Nature

Thyroid nodules in Graves disease and the risk of thyroid carcinoma

Background: The risk of thyroid carcinoma in patients with Graves disease has been particularly emphasized when nodules coexist with thyroid hyperplasia; a surgical approach has been suggested. Objectives: To detect thyroid nodules early in patients with Graves disease and to evaluate the risk of carcinoma. Methods: The study group included 315 consecutive outpatients with Graves hyperthyroidism not previously treated with surgery or radioiodine therapy. Thyroid ultrasonography was performed at the time of enrollment and repeated annually in all patients; fine-needle aspiration (FNA) was carried out in those patients with nodules and repeated after 2 years or at shorter intervals. Results: One hundred six of 315 patients with Graves disease had thyroid nodules 8 mm in diameter or larger detected by ultrasonography. In 49 patients, nodules were present at the time of the first examination; in 57 patients, nodules developed during follow-up. Fine- needle aspiration cytology results revealed features of carcinoma in only 1 patient; this was confirmed by histologic examination of excised thyroid tissue. The nodules with normal cytologic features at the time of the first examination did not show any clinical and/or cytologic evolution toward malignancy during follow-up. Conclusions: Ultrasonographic evidence of nodules was frequently found among our patients with Graves disease, but malignant FNA cytologic findings of the examined nodules were rare at the time of diagnosis and throughout the course of the disease. When FNA cytologic evaluation does not indicate malignancy, the presence of thyroid nodules in patients with Graves disease does not indicate an aggressive therapeutic approach

Human lymphocyte antigens in Graves'disease : correlation with persistent course of disease

Graves' disease is a thyroid autoimmune disorder associated with specific human lymphocyte antigen (HLA) alleles, characterized by an unpredictable long-term course. To investigate possible relations between HLA phenotype and outcome of the disease, the authors typed for HLA antigens in 105 patients with Graves' disease with different course of disease. All patients were treated with antithyroid drugs for at least 12 months; 29 patients had stable remission 24 or more months after withdrawal of treatment; 76 patients had persistent disease--66 unremitting/relapsing hyperthyroidism, 10 stable hypothyroidism--36 or more months after onset of disease. The following findings emerged from this study: 1) HLA B8 and DR3 were increased significantly in Graves' patients versus 6,682 control subjects from the same geographic area (23.80% vs 12.01%, odds ratio [OR] 1.98, and 31.43% vs 18.00%, OR 1.75, respectively); the antigen combinations B8-DR3, B8-Cw7-DR3, and A1-B8-Cw7-DR3 were significantly more frequent in Graves' patients vs control subjects; in addition, these combinations were present exclusively in patients with persistent disease (B8-DR3 28.95%, OR 7.14, B8-Cw7-DR3 27.63%, OR 11.24, and A1-B8-Cw7-DR3 18.42%, OR 11.29). These data provide evidence that not only susceptibility to Graves' disease, but also persistent activity of the autoimmune process, producing either hyperthyroidism or stable hypothyroidism, is associated with specific HLA antigen phenotypes