Effect of Postextubation High-Flow Nasal Cannula vs Conventional Oxygen Therapy on Reintubation in Low-Risk Patients: A Randomized Clinical Trial.

IMPORTANCE: Studies of mechanically ventilated critically ill patients that combine populations that are at high and low risk for reintubation suggest that conditioned high-flow nasal cannula oxygen therapy after extubation improves oxygenation compared with conventional oxygen therapy. However, conclusive data about reintubation are lacking. OBJECTIVE: To determine whether high-flow nasal cannula oxygen therapy is superior to conventional oxygen therapy for preventing reintubation in mechanically ventilated patients at low risk for reintubation. DESIGN, SETTING, AND PARTICIPANTS: Multicenter randomized clinical trial conducted between September 2012 and October 2014 in 7 intensive care units (ICUs) in Spain. Participants were 527 adult critical patients at low risk for reintubation who fulfilled criteria for planned extubation. Low risk for reintubation was defined as younger than 65 years; Acute Physiology and Chronic Health Evaluation II score less than 12 on day of extubation; body mass index less than 30; adequate secretions management; simple weaning; 0 or 1 comorbidity; and absence of heart failure, moderate-to-severe chronic obstructive pulmonary disease, airway patency problems, and prolonged mechanical ventilation. INTERVENTIONS: Patients were randomized to undergo either high-flow or conventional oxygen therapy for 24 hours after extubation. MAIN OUTCOMES AND MEASURES: The primary outcome was reintubation within 72 hours, compared with the Cochran-Mantel-Haenszel χ2 test. Secondary outcomes included postextubation respiratory failure, respiratory infection, sepsis and multiorgan failure, ICU and hospital length of stay and mortality, adverse events, and time to reintubation. RESULTS: Of 527 patients (mean age, 51 years [range, 18-64]; 62% men), 264 received high-flow therapy and 263 conventional oxygen therapy. Reintubation within 72 hours was less common in the high-flow group (13 patients [4.9%] vs 32 [12.2%] in the conventional group; absolute difference, 7.2% [95% CI, 2.5% to 12.2%]; P = .004). Postextubation respiratory failure was less common in the high-flow group (22/264 patients [8.3%] vs 38/263 [14.4%] in the conventional group; absolute difference, 6.1% [95% CI, 0.7% to 11.6%]; P = .03). Time to reintubation was not significantly different between groups (19 hours [interquartile range, 12-28] in the high-flow group vs 15 hours [interquartile range, 9-31] in the conventional group; absolute difference, -4 [95% CI, -54 to 46]; P = .66]. No adverse effects were reported. CONCLUSIONS AND RELEVANCE: Among extubated patients at low risk for reintubation, the use of high-flow nasal cannula oxygen compared with conventional oxygen therapy reduced the risk of reintubation within 72 hours. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01191489.

Effect of Postextubation High-Flow Nasal Cannula vs Noninvasive Ventilation on Reintubation and Postextubation Respiratory Failure in High-Risk Patients: A Randomized Clinical Trial.

Importance: High-flow conditioned oxygen therapy delivered through nasal cannulae and noninvasive mechanical ventilation (NIV) may reduce the need for reintubation. Among the advantages of high-flow oxygen therapy are comfort, availability, lower costs, and additional physiopathological mechanisms. Objective: To test if high-flow conditioned oxygen therapy is noninferior to NIV for preventing postextubation respiratory failure and reintubation in patients at high risk of reintubation. Design, Setting, and Participants: Multicenter randomized clinical trial in 3 intensive care units in Spain (September 2012-October 2014) including critically ill patients ready for planned extubation with at least 1 of the following high-risk factors for reintubation: older than 65 years; Acute Physiology and Chronic Health Evaluation II score higher than 12 points on extubation day; body mass index higher than 30; inadequate secretions management; difficult or prolonged weaning; more than 1 comorbidity; heart failure as primary indication for mechanical ventilation; moderate to severe chronic obstructive pulmonary disease; airway patency problems; or prolonged mechanical ventilation. Interventions: Patients were randomized to undergo either high-flow conditioned oxygen therapy or NIV for 24 hours after extubation. Main Outcomes and Measures: Primary outcomes were reintubation and postextubation respiratory failure within 72 hours. Noninferiority margin was 10 percentage points. Secondary outcomes included respiratory infection, sepsis, and multiple organ failure, length of stay and mortality; adverse events; and time to reintubation. Results: Of 604 patients (mean age, 65 [SD, 16] years; 388 [64%] men), 314 received NIV and 290 high-flow oxygen. Sixty-six patients (22.8%) in the high-flow group vs 60 (19.1%) in the NIV group were reintubation (absolute difference, -3.7%; 95% CI, -9.1% to ∞); 78 patients (26.9%) in the high-flow group vs 125 (39.8%) in the NIV group experienced postextubation respiratory failure (risk difference, 12.9%; 95% CI, 6.6% to ∞) [corrected]. Median time to reintubation did not significantly differ: 26.5 hours (IQR, 14-39 hours) in the high-flow group vs 21.5 hours (IQR, 10-47 hours) in the NIV group (absolute difference, -5 hours; 95% CI, -34 to 24 hours). Median postrandomization ICU length of stay was lower in the high-flow group, 3 days (IQR, 2-7) vs 4 days (IQR, 2-9; P=.048). Other secondary outcomes were similar in the 2 groups. Adverse effects requiring withdrawal of the therapy were observed in none of patients in the high-flow group vs 42.9% patients in the NIV group (P < .001). Conclusions and Relevance: Among high-risk adults who have undergone extubation, high-flow conditioned oxygen therapy was not inferior to NIV for preventing reintubation and postextubation respiratory failure. High-flow conditioned oxygen therapy may offer advantages for these patients. Trial Registration: clinicaltrials.gov Identifier: NCT01191489.

EPHA7, a new target gene for 6q deletion in T-cell lymphoblastic lymphomas.

Cryptic deletions at chromosome 6q are common cytogenetic abnormalities in T-cell lymphoblastic leukemia/lymphoma (T-LBL), but the target genes have not been formally identified. Our results build on detection of specific chromosomal losses in a mouse model of γ-radiation-induced T-LBLs and provide interesting clues for new putative susceptibility genes in a region orthologous to human 6q15-6q16.3. Among these, Epha7 emerges as a bona fide candidate tumor suppressor gene because it is inactivated in practically all the T-LBLs analyzed (100% in mouse and 95.23% in human). We provide evidence showing that Epha7 downregulation may occur, at least in part, by loss of heterozygosity (19.35% in mouse and 12.5% in human) or promoter hypermethylation (51.61% in mouse and 43.75% in human) or a combination of both mechanisms (12.90% in mouse and 6.25% in human). These results indicate that EPHA7 might be considered a new tumor suppressor gene for 6q deletions in T-LBLs. Notably, this gene is located in 6q16.1 proximal to GRIK2 and CASP8AP2, other candidate genes identified in this region. Thus, del6q seems to be a complex region where inactivation of multiple genes may cooperatively contribute to the onset of T-cell lymphomas.

Benefit with preventive noninvasive ventilation in subgroups of patients at high-risk for reintubation: a post hoc analysis.

BACKGROUND: High-flow nasal cannula (HFNC) was shown to be non-inferior to noninvasive ventilation (NIV) for preventing reintubation in a general population of high-risk patients. However, some subgroups of high-risk patients might benefit more from NIV. We aimed to determine whether the presence of many risk factors or overweight (body mass index (BMI) ≥ 25 kg/m2) patients could have different response to any preventive therapy, NIV or HFNC in terms of reduced reintubation rate. METHODS: Not pre-specified post hoc analysis of a multicentre, randomized, controlled, non-inferiority trial comparing NFNC and NIV to prevent reintubation in patients at risk for reintubation. The original study included patients with at least 1 risk factor for reintubation. RESULTS: Among 604 included in the original study, 148 had a BMI ≥ 25 kg/m2. When adjusting for potential covariates, patients with ≥ 4 risk factors (208 patients) presented a higher risk for reintubation (OR 3.4 [95%CI 2.16-5.35]). Patients with ≥ 4 risk factors presented lower reintubation rates when treated with preventive NIV (23.9% vs 45.7%; P = 0.001). The multivariate analysis of overweight patients, adjusted for covariates, did not present a higher risk for reintubation (OR 1.37 [95%CI 0.82-2.29]). However, those overweight patients presented an increased risk for reintubation when treated with preventive HFNC (OR 2.47 [95%CI 1.18-5.15]). CONCLUSIONS: Patients with ≥ 4 risk factors for reintubation may benefit more from preventive NIV. Based on this result, HFNC may not be the optimal preventive therapy in overweight patients. Specific trials are needed to confirm these results.

Early Tracheostomy for Managing ICU Capacity During the COVID-19 Outbreak: A Propensity-Matched Cohort Study.

BACKGROUND: During the first wave of the COVID-19 pandemic, shortages of ventilators and ICU beds overwhelmed health care systems. Whether early tracheostomy reduces the duration of mechanical ventilation and ICU stay is controversial. RESEARCH QUESTION: Can failure-free day outcomes focused on ICU resources help to decide the optimal timing of tracheostomy in overburdened health care systems during viral epidemics? STUDY DESIGN AND METHODS: This retrospective cohort study included consecutive patients with COVID-19 pneumonia who had undergone tracheostomy in 15 Spanish ICUs during the surge, when ICU occupancy modified clinician criteria to perform tracheostomy in Patients with COVID-19. We compared ventilator-free days at 28 and 60 days and ICU- and hospital bed-free days at 28 and 60 days in propensity score-matched cohorts who underwent tracheostomy at different timings (≤ 7 days, 8-10 days, and 11-14 days after intubation). RESULTS: Of 1,939 patients admitted with COVID-19 pneumonia, 682 (35.2%) underwent tracheostomy, 382 (56%) within 14 days. Earlier tracheostomy was associated with more ventilator-free days at 28 days (≤ 7 days vs > 7 days [116 patients included in the analysis]: median, 9 days [interquartile range (IQR), 0-15 days] vs 3 days [IQR, 0-7 days]; difference between groups, 4.5 days; 95% CI, 2.3-6.7 days; 8-10 days vs > 10 days [222 patients analyzed]: 6 days [IQR, 0-10 days] vs 0 days [IQR, 0-6 days]; difference, 3.1 days; 95% CI, 1.7-4.5 days; 11-14 days vs > 14 days [318 patients analyzed]: 4 days [IQR, 0-9 days] vs 0 days [IQR, 0-2 days]; difference, 3 days; 95% CI, 2.1-3.9 days). Except hospital bed-free days at 28 days, all other end points were better with early tracheostomy. INTERPRETATION: Optimal timing of tracheostomy may improve patient outcomes and may alleviate ICU capacity strain during the COVID-19 pandemic without increasing mortality. Tracheostomy within the first work on a ventilator in particular may improve ICU availability.

Lack of association of SNPs from the FADS1-FADS2 gene cluster with major depression or suicidal behavior.

Fatty acid desaturase genes (FADS1-FADS2) encode desaturases participating in the biosynthesis of long-chain polyunsaturated fatty acids. As long-chain polyunsaturated fatty acids are implicated in major depressive disorder (MDD) and suicide risk, and as both are partly heritable, we studied the association of FADS1-FADS2 polymorphisms with MDD (635 cases, 480 controls) and suicide attempt status (291 attempters, 344 MDD nonattempters). Eighteen FADS-related single-nucleotide polymorphisms were genotyped from Caucasians enrolled in Madrid (n=791) or New York City (n=324) and entered as predictors into logistic regression analyses with diagnostic group or suicide attempt history as outcomes and location and sex as covariates. No associations were observed between any single-nucleotide polymorphisms and diagnosis or attempt status. As statistical power was adequate, we conclude that FADS1-FADS2 genetic variants may not be a common determinant of MDD.

A new locus for resistance to gamma-radiation-induced thymic lymphoma identified using inter-specific consomic and inter-specific recombinant congenic strains of mice.

Mice of the C57BL/6J inbred strain develop thymic lymphomas at very high frequency after acute gamma-irradiation, while mice of several inbred strains derived from the wild progenitor of the Mus spretus species and their F1 hybrids with C57BL/6J appear extremely resistant. Analysis of the genetic determinism of the gamma-radiation-induced thymic lymphoma (RITL) resistance with the help of inter-specific consomic strains (ICS), which carry a single introgressed Mus spretus chromosome on a C57BL/6J genetic background, provide significant evidence for the existence of a thymic lymphoma resistance (Tlyr1) locus on chromosome 19. The subsequent analysis of the backcross progeny resulting from a cross between consomic mice heterozygous for the Mus spretus chromosome 19 and C57BL/6J mice, together with the study of inter-specific recombinant congenic strains (IRCS), suggest that this Tlyr1 locus maps within the D19Mit60-D19Mit40 chromosome interval. In addition to the discovery of a new locus controlling RITL development, our study emphasizes the value of ICS and IRCS for the genetic analysis of cancer predisposition.

A gender-specific association between the serotonin transporter gene and suicide attempts.

This pilot study tested the gender-specificity of the association between suicide attempts and a polymorphism in the promoter area of the serotonin transporter with two allelic variants, a long (1) variant and a short (s) variant. In a Spanish general hospital, 180 suicide attempters (121 women and 59 men) and 212 control blood donors (93 women and 119 men) were recruited. Subjects were classified as S individuals (s/s or s/l) with low expression of the serotonin transporter, and L individuals (l/l) with high expression. S individuals were significantly overrepresented (or L, underrepresented) in female attempters when compared with female controls and male attempters. Lethality appeared to have a significant influence on the effects of the genotype in suicide since S females were overrepresented among non-lethal female attempters. Further studies are needed to replicate that the serotonin genotype polymorphism may influence suicide attempts only in females.

Lack of association between polymorphic variations in the alpha 3 subunit GABA receptor gene (GABRA3) and suicide attempts.

This is the first case-control study exploring the association between suicide attempts and the polymorphic variations of the alpha 3 subunit gamma-aminobutyric acid (GABA) receptor gene (GABRA3) located in chromosome X. In a Spanish general hospital, 184 suicide attempters (127 women and 57 men) and 275 control blood donors (109 women and 166 men) were recruited. The four frequent variants (A1, A2, A3 and A4) of GABRA3 were studied. There were no significant differences in the total or by-gender frequencies of the four alleles. In females, there were no significant differences in the genotypes. This study can rule out even small size effects in the total sample and suggests a lack of association between GABRA3 polymorphism and suicide attempt, in the Spanish population.

Lack of association between the serotonin transporter promoter gene polymorphism and impulsivity or aggressive behavior among suicide attempters and healthy volunteers.

The association between a polymorphism in the promoter area of the serotonin transporter (17q11.1-q12) with impulsivity and history of aggressive behavior was studied in a Spanish general hospital. Subjects comprised 216 suicide attempters (152 women and 64 men) and 223 control blood donors (124 women and 99 men). They were classified as S individuals (s/s or s/l) with low expression of the serotonin transporter, and L individuals (l/l) with high expression. The genotype was not associated with high levels of impulsivity (measured with the Barratt Impulsiveness Scale) or history of aggressive behavior (measured with the Brown-Goodwin scale). This lack of association did not appear to be explained by lack of statistical power. High scores on the Barratt Impulsiveness Scale (BIS) and the Brown-Goodwin Aggressive Behavior Scale were associated with being an attempter, male gender and borderline personality disorder. While our Spanish suicide attempters and published US suicide attempters have similar BIS scores, our Spanish suicide attempters have significantly lower aggressive behavior scores. If cross-cultural differences in aggressive behavior scores are definitively established, country norms for aggressive behavior scales will need to be developed to compare genetic studies in different countries.

Extensive genotyping of the BDNF and NTRK2 genes define protective haplotypes against obsessive-compulsive disorder.

BACKGROUND: Family, twin and molecular studies provide increasing evidence for the importance of genetic factors in obsessive-compulsive disorder (OCD). Recent work suggests that brain-derived neurotrophic factor (BDNF) may be involved in OCD pathophysiology. We used a linkage disequilibrium (LD)-mapping approach to investigate the role that BDNF and its specific receptor neurotrophic tyrosine kinase receptor type 2 (NTRK2) may play in increasing susceptibility to OCD. METHODS: Eight tag single nucleotide polymorphisms (tagSNPs) covering the BDNF gene region and 46 tagSNPs in the NTRK2 region were genotyped in 215 OCD patients and 342 control subjects. Single nucleotide polymorphism association and haplotype analysis were performed. The possible relationship between genetic factors and clinical characteristics including age of OCD onset, tic disorders, clinical dimensions, and family history of OCD were investigated. RESULTS: Haplotype analysis revealed a significant association between OCD and a five-marker protective haplotype located toward the 5' of the BDNF gene (odds ratio [OR] = .80; 95% confidence interval [CI] = .69-.92; permutation p value = .006) containing the functional valine (Val)66-to-methionine (Met) variant. A significant association between a NTRK2 intronic SNP (rs2378672) and OCD was identified (p < .0001) in female patients under an additive model. A protective haplotype located in intron 19 of NTRK2 was also associated with OCD (OR = .76; 95% CI = .66-.87; permutation p value = .001). CONCLUSIONS: These findings support a role for the BDNF/NTRK2 signaling pathway in genetic susceptibility to OCD.

A pilot study on a gene-hormone interaction in female suicide attempts.

This one-year naturalistic study included all suicide attempters in a catchment area. In the first published set of analyses, an association between menses and suicide attempts was replicated. According to the polymorphism of the serotonin transporter promoter area, the subjects can be classified as S individuals (s/s or s/l) or L individuals (l/l). In the second published set of analyses, L females appeared protected from suicide attempts since they were underrepresented among female (and not male) attempters. This new, unpublished third set of analyses tested for an interaction between the same polymorphism and low hormonal activity (during menses and menopause). In fertile female attempters, the proportion of L women in the menses (41%, 7/17) was significantly higher than expected in the population (15.5 %) and almost significantly higher than in S female attempters (22%,19/87). L females were also overrepresented in postmenopausal attempters. Despite sample size limitations, this gene-hormone interaction needs to be further investigated in female suicide attempters.

Lack of correlation between DNA copy number and mRNA expression levels of c-myc in gamma-radiation-induced mouse thymic lymphomas by using quantitative real-time PCR

Background. It is well documented that over-expressionof the c-myc proto-oncogene occurs in thevast majority of mouse thymic lymphomas inducedby gamma-irradiation, evidencing the importance of thisgene in T-cell lymphomagenesis. However, it remainsunknown whether elevated levels of c-mycexpression are driven by extra c-myc copy numbers.Materials and methods. Here we use a quantitativetest on the basis of real-time PCR to determine thecellular copy number of c-myc in a set of 14 g-radiation-induced thymic lymphomas obtained from(C57BL/6J x BALB/cJ) F1 hybrid mice with increasedmRNA c-myc expression.Results. Since 5 out of 14 (35.7%) cases had no extracopy numbers of c-myc, gene amplification was obviouslynot the cause of c-myc over-expression inthese tumours. In the remaining 9 tumours, c-mycover-expression was also accompanied with extraDNA copy numbers. Therefore, c-myc amplificationmight be a consequence of the genomic instabilitysubsequent to the up-regulation of c-myc. However,linear regression analysis showed a lack of correlationbetween increasing DNA copy numbers andmRNA over expression of c-myc in these tumours (r= 0.029, p = 0.94).Conclusion. De-regulation of c-myc does not necessarilyimply amplification of this gene in these tumours.This report is, to our knowledge, the firstone comparing c-myc amplification with expressionin lymphomas of the T-cell lineage

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