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Hypothermia or Normothermia after Cardiac ArrestThis trial randomly assigned patients with coma after out-of-hospital cardiac arrest to undergo targeted hypothermia at 33 degrees C or normothermia with treatment of fever. At 6 months, there were no significant between-group differences regarding death or functional outcomes.BackgroundTargeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty.MethodsIn an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33 degrees C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, >= 37.8 degrees C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device.ResultsA total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P=0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score >= 4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, PConclusionsIn patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, .)

Purpose The Gruppo Oncologico Nord Ovest (GONO) conducted a phase III study comparing fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI [irinotecan 165 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, leucovorin 200 mg/m2 day 1, fluorouracil 3,200 mg/m2 48-hour continuous infusion starting on day 1, every 2 weeks]) with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI). Methods Selection criteria included unresectable metastatic colorectal cancer, age 18 to 75 years, and no prior chemotherapy for advanced disease. The primary end point was response rate (RR). Results A total of 244 patients were randomly assigned. An increase of grade 2 to 3 peripheral neurotoxicity (0% v 19%; P < .001), and grade 3 to 4 neutropenia (28% v 50%; P < .001) were observed in the FOLFOXIRI arm. The incidence of febrile neutropenia (3% v 5%) and grade 3 to 4 diarrhea (12% v 20%) were not significantly different. Responses, as assessed by investigators, were, for FOLFIRI and FOLFOXIRI, respectively, complete, 6% and 8%; and partial, 35% and 58%, (RR, 41% v 66%; P = .0002). RR confirmed by an external panel was 34% versus 60% (P < .0001). The R0 secondary resection rate of metastases was greater in the FOLFOXIRI arm (6% v 15%; P = .033, among all 244 patients; and 12% v 36%; P = .017 among patients with liver metastases only). Progression-free survival (PFS) and overall survival (OS) were both significantly improved in the FOLFOXIRI arm (median PFS, 6.9 v 9.8 months; hazard ratio [HR], 0.63; P = .0006; median OS, 16.7 v 22.6 months; HR, 0.70; P = .032). Conclusion The FOLFOXIRI regimen improves RR, PFS, and OS compared with FOLFIRI, with an increased, but manageable, toxicity in patients with metastatic colorectal cancer with favorable prognostic characteristics. Further studies of FOLFOXIRI in combination with targeted agents and in the neoadjuvant setting are warranted.

Twenty-two patients with metastatic colorectal cancer entered a Phase I-II trial to assess the maximum tolerable dose of alpha-2B-interferon administered intramuscularly three times per week in combination with fixed doses of 5-fluorouracil (450 mg/m2 IV for 5 days, and, from day 28, weekly) and folinic acid (200 mg/m2 IV before 5-fluorouracil) and the efficacy of this combination. Diarrhea and mucositis were the most frequent 5-fluorouracil-related toxicities and wereor = ECOG grade 3 in 23% and 18% of patients, respectively. Of 15 patients receiving interferonor = 9 x 10(6) IU, 10 required interferon dose reduction mostly because of severe fatigue, anorexia, and declining performance status. Among 19 patients evaluable for response, 3 achieved a partial response and 1 a complete response for an overall response rate of 21% (95% confidence interval, 6-46%). In conclusion, our study demonstrates that IFN-alpha 2B at doses higher than 6 x 10(6) IU intramuscularly three times per week in the combination with 5-fluorouracil and folinic acid we used is too toxic for the majority of patients; this combination has moderate activity in metastatic colorectal cancer, although similar response rates have been reported, with less toxicity, with 5-fluorouracil plus folinic acid without IFN-alpha. A larger Phase III study would be required to determine the value of IFN-alpha in this combination.

Experimental studies have demonstrated that 5-fluorouracil (5-FU) enhances zidovudine (AZT)-induced DNA strand breaks and cytotoxicity. Phase I studies have demonstrated that the maximum tolerable dose (MTD) of AZT is 8000 mg/sqm when administered i.v. over two hours after weekly 5-FU + l-leucovorin (LV), and that this combination has promising antitumor activity. The purpose of this study was therefore to evaluate the antitumor activity of weekly bolus 5-FU + LV + AZT, administered at its MTD, and to determine whether 5-FU enhances AZT-induced DNA strand breaks in blood nuclear cells.Twenty-nine chemotherapy-naïve metastatic colorectal cancer patients with measurable disease entered the study to evaluate the activity of a weekly 5-FU 500 mg/m2 i.v. bolus + LV 250 mg/m2 i.v. two-hour infusion + AZT 8000 mg/m2 i.v. two-hour infusion. In 10 different patients, who during three different weeks received 5-FU + LV, AZT and 5-FU + LV + AZT, DNA strand breaks in blood nuclear cells were determined by a fluorescent analysis of DNA unwinding.Treatment was generally well tolerated and WHO grades III-IV toxicities, consisting mostly of diarrhea (17%), were uncommon. One patient died of severe diarrhea with consequent hypokalemia and cardiac arrhythmia. All patients were considered evaluable for response, and 3 (10%) complete and 10 (35%) partial responses were observed, for an objective response rate of 45% (95% confidence limit interval 26%-64%). Both 5-FU + LV and AZT decreased the percentage of double stranded DNA in nuclear blood cells. The greatest effect was observed with 5-FU + LV + AZT, which reduced the percentage of double stranded DNA to 50% and 36% after 24 and 48 hours, respectively, and this interaction between 5-FU + LV and AZT was found to be cumulative.These studies demonstrate that the present dose and schedule of AZT in combination with 5-FU + LV has significant activity in metastatic colorectal cancer and that the combination of 5-FU + LV with AZT increases the amount of DNA damage. Therefore, AZT in combination with 5-FU + LV warrants further study in colorectal cancer.

Critically ill patients in Intensive Care Unit (ICU), due to their temporary or permanent incompetence, are often not capable to provide informed consent (IC), although required, for not emergency invasive procedures, like elective tracheostomy. By Italian law, a person with partially/temporarily physical/mental impairment needs a legal tutorship appointed by the court (Support Administrator, SA). We performed a national survey in Italy to investigate IC practice for elective tracheostomy procedure in critically ill conscious and unconscious patients in ICU.Questions about IC were included in a survey concerning the clinical practice of tracheostomy in ICU. The survey was approved by the Italian Society of Anesthesia, Analgesia and Intensive Care (SIAARTI, n° 434 - 28 March 2012) and sent by e-mail to all members included in its mailing list. The duration of the survey was three months from April to June 2012. All required information was referred to the year 2011.The mailed questionnaire correctly fulfilled was sent back by 131/427 (30%) national ICUs. Our data showed 1) in conscious patients, IC was obtained by 82.4% of ICUs; 2) in unconscious patients, IC was obtained in only 61.8% with different procedures not following the current Italian law, 3) for surgical tracheostomy performed in operating room, IC was obtained in conscious and unconscious patients in only 69.8% and 47.2% of ICUs, respectively, 4) risk/benefit informative document was provided in 61.1% ICUs, but available only in 47.2% of ICUs performing tracheostomy in operating room.In Italian ICUs, participating to this study, the procedures related to IC for conscious and unconscious critically ill patients requiring surgical or percutaneous tracheostomy are not in line with current legal rules and procedures.

BRCA1 germline mutations confer susceptibility to familial breast and ovarian cancer. Mutational hot spots have never been detected in BRCA1 cDNA. Some mutations have been reported several times whereas some others appear to be population-related. In this study a group of 36 Italian families were analysed for BRCA1 germline mutations. All of them were screened by allele-specific oligonucleotide hybridization (ASO) for three recurrent mutations (185delAG, 5382insC, nt332-TG). Twenty families, selected because of their high risk of carrying BRCA1 mutations, were subjected to analysis of the entire coding sequence of the gene. A total of eight mutations were found. ASO screening demonstrated only one known mutation in one patient, whereas cycle sequencing revealed five new mutations. Three of these new mutations were frameshifts: one occurred in exon 11 (1499insA), one in exon 16 (4873delCA) and one in the splice site of exon 3 (252delAAgt). Two were missense mutations (Cys64Arg; Asn158Tyr). The same frameshift mutation, 1499insA, was detected in three unrelated families. Haplotype analysis supported the hypothesis that two of these families may have had common ancestors, whereas in the third family the analysis was uninformative. BRCA1 germline mutations were found in one out of two families with ovarian cancer, in five out of eight families with breast-ovarian cancer, and in two out of 11 families with breast cancer. All three families with 1499insA mutations included at least one case of ovarian cancer. The majority of the ovarian cancers (4/5) associated with detectable BRCA1 germline mutations were of serous histotype.

The mortality of postcardiac arrest patients has gradually reduced in years but it still is as high as 50%, despite advancements in the diagnostic and therapeutic approaches, i.e. revascularization and therapeutic moderate hypothermia. However, recent evidence suggests that other therapeutic interventions aimed to minimize progressive deterioration of the brain and other organs function might be helpful to reduce in-hospital mortality and improve neurologic outcome as well as quality of life after cardiac arrest. In this article, we discuss the role of ventilator management on the prognosis after cardiac arrest. We performed a meta-analysis showing that in adult patients not only hypoxia but also hyperoxia was associated with higher in-hospital mortality, while hypercapnia and hypocapnia worse neurologic outcome. In pediatric patients, hypoxia and hyperoxia were not associated with higher in-hospital mortality, while hypocapnia and hypercabia with higher in-hospital mortality worse neurologic outcome. We propose a general bundle for ventilator treatment after cardiac arrest, including: 1) therapeutic hypothermia for 12-24 hours; 2) mean arterial pressure ≥65-75 mmHg; 3) PaO2 between 60-200 mmHg and PCO2 between 30 and 50 mmHg; 4) protective MV with tidal volume of 6-8 mL/kg and positive end expiratory pressure of between 5-10 cmH2O; 5) monitoring of respiratory mechanics, extravascular lung water, hemodynamics, non-invasive transcranial Doppler and intracranial pressure monitoring; and 6) others supportive care, i.e. blood sugar and seizures control.

The influence of various patient and disease-related parameters on survival (S) and disease-free survival (DFS) in 217 node positive primary breast cancer patients treated with surgery followed by adjuvant i.v. cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) was evaluated by univariate and multivariate analyses. Five year actuarial S and DFS were 73.3% and 54.8%, respectively. Univariate analysis revealed that patient age, number of involved axillary nodes and ER status had a significant impact on both S and DFS. PgR positive tumors had improved DFS but no S difference was observed. Menopausal status predicted S but not DFS. Primary tumor size and CMF-induced amenorrhea did not predict disease outcome. Multivariate analysis demonstrated that only degree of nodal involvement and PgR status had independent significant impact on prognosis. Both S and DFS are significantly influenced by the number of involved nodes, whereas improved DFS but not S was evident in patients with PgR positive tumors.

This study aims to identify the main determinants of students' performances in reading and maths across eight European Union countries (i.e. Austria, Croatia, Germany, Hungary, Italy, Portugal, Slovakia, and Slovenia). Based on student level data from the OECD-PISA 2018 survey and by means of the application of efficient algorithms, we highlight that the number of books at home or a variable combining the type and location of school represent the most important predictors of the students' performance in all the analysed countries, while other school characteristics are rarely relevant. Econometric results show that students attending vocational schools perform significantly worse than those in general schools. Looking at differences between students attending schools in big cities and those in small cities, they are never statistically significant except in Portugal. Through the Gelbach decomposition method, which allows to measure the relative importance of observable characteristics to explain a gap, we show that the differences in test scores between big and small cities depend on the schools' characteristics, while the differences between general and vocational schools are mainly explained by the families' social status. Results appear robust to the hierarchical model approach.

The issue of Student Evaluation of Teaching has been explored by a large literature across many decades. However, the role of social influence factors in determining teachers’ responses to a given incentive and evaluation framework has been left basically unexplored. This paper makes a first attempt in this vein by considering an evolutionary game-theoretic context where teachers face a two-stage process in which their rating depends on both students’ evaluation of their course and on retrospective students’ evaluation of their teaching output in view of students’ performance in a related follow-up course. We find that both high effort (difficult course offered) and low effort (easy course offered) outcomes may emerge, leading either to a socially optimal outcome for teachers or not, according to cases. Moreover, there may be a potential conflict between the optimal outcome for students and for teachers. We also consider possible ways to generalize our model in future research.

BACKGROUND: Percutaneous dilational tracheostomy is normally a bronchoscope-guided procedure. The insertion of a bronchoscope into an endotracheal tube (ETT) affects resistance, flow, and alveolar pressure. To improve airway management and ventilation during percutaneous tracheostomy, we developed a double lumen endotracheal tube (DLET). The aim of this in vitro study was to compare the linear constant of the Rohrer equation (K1), the nonlinear constant of the Rohrer equation (K2), the inspiratory and expiratory airway resistance, and ventilatory and airway pressures using the DLET with different standard sized ETTs. METHODS: A trachea and lung model was used to compare the DLET to ETTs with 7, 7.5, and 8 mm inner diameters with and without a bronchoscope (4.5 mm external diameter), and 4 and 5 mm inner diameter ventilation tubes (F4, F5) of a translaryngeal tracheostomy. For each device, the pressure drop across the device and the Rohrer equation linear constant (K1) and nonlinear constant (K2) were calculated during a continuous flow of 10–90 L/min, the inspiratory and expiratory airway resistance values were calculated during volume controlled mechanical ventilation, and respiratory airway pressure values were calculated during volume and pressure controlled mechanical ventilation. RESULTS: DLET had lower K2, pressure drop, and inspiratory and expiratory airway resistance compared with conventional ETTs plus fiberoptic bronchoscope. Furthermore, during mechanical ventilation, DLET had a lower value of peak pressure, mean pressure, and intrinsic PEEP than the other ETTs plus fiberoptic bronchoscope. CONCLUSIONS: Use of the DLET during percutaneous dilational tracheostomy allows fiberoptic bronchoscopy without imposing excessive airway resistance. Reduced tube resistance during this procedure may confer additional safety in what is well known to be a hazardous procedure.