BACKGROUND

The clinically appropriate range for oxygen saturation in preterm infants is unknown. Previous studies have shown that infants had reduced rates of retinopathy of prematurity when lower targets of oxygen saturation were used.

METHODS
In three international randomized, controlled trials, we evaluated the effects of targeting an oxygen saturation of 85 to 89%, as compared with a range of 91 to 95%, on disability-free survival at 2 years in infants born before 28 weeks' gestation. Halfway through the trials, the oximeter-calibration algorithm was revised. Recruitment was stopped early when an interim analysis showed an increased rate of death at 36 weeks in the group with a lower oxygen saturation. We analyzed pooled data from patients and now report hospital-discharge outcomes.

RESULTS
A total of 2448 infants were recruited. Among the 1187 infants whose treatment used the revised oximetercalibration algorithm, the rate of death was significantly higher in the lower-target group than in the highertarget group (23.1% vs. 15.9%; relative risk in the lower-target group, 1.45; 95% confidence interval [CI], 1.15 to 1.84; P=0.002). There was heterogeneity for mortality between the original algorithm and the revised algorithm (P=0.006) but not for other outcomes. In all 2448 infants, those in the lower-target group for oxygen saturation had a reduced rate of retinopathy of prematurity (10.6% vs. 13.5%; relative risk, 0.79; 95% CI, 0.63 to 1.00; P=0.045) and an increased rate of necrotizing enterocolitis (10.4% vs. 8.0%; relative risk, 1.31; 95% CI, 1.02 to 1.68; P=0.04). There were no significant between-group differences in rates of other outcomes or adverse events.

CONCLUSIONS
Targeting an oxygen saturation below 90% with the use of current oximeters in extremely preterm infants was associated with an increased risk of death. (Funded by the Australian National Health and Medical Research Council and others; BOOST II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry numbers, ACTRN12605000055606and ACTRN12605000253606.)

denotonsillectomy is commonly performed in children with the obstructive sleep apnea syndrome, yet its usefulness in reducing symptoms and improving cognition, behavior, quality of life, and polysomnographic findings has not been rigorously evaluated. We hypothesized that, in children with the obstructive sleep apnea syndrome without prolonged oxyhemoglobin desaturation, early adenotonsillectomy, as compared with watchful waiting with supportive care, would result in improved outcomes.

Full Text of Background...

METHODS

We randomly assigned 464 children, 5 to 9 years of age, with the obstructive sleep apnea syndrome to early adenotonsillectomy or a strategy of watchful waiting. Polysomnographic, cognitive, behavioral, and health outcomes were assessed at baseline and at 7 months.

Full Text of Methods...

RESULTS
The average baseline value for the primary outcome, the attention and executive-function score on the Developmental Neuropsychological Assessment (with scores ranging from 50 to 150 and higher scores indicating better functioning), was close to the population mean of 100, and the change from baseline to follow-up did not differ significantly according to study group (mean [SD] improvement, 7.113.9 in the early-adenotonsillectomy group and 5.113.4 in the watchful-waiting group; P=0.16). In contrast, there were significantly greater improvements in behavioral, quality-of-life, and polysomnographic findings and significantly greater reduction in symptoms in the early-adenotonsillectomy group than in the watchfulwaiting group. Normalization of polysomnographic findings was observed in a larger proportion of children in the early-adenotonsillectomy group than in the watchful-waiting group (79% vs. 46%).

Full Text of Results...

CONCLUSIONS
As compared with a strategy of watchful waiting, surgical treatment for the obstructive sleep apnea syndrome in school-age children did not significantly improve attention or executive function as measured by neuropsychological testing but did reduce symptoms and improve secondary outcomes of behavior, quality of life, and polysomnographic findings, thus providing evidence of beneficial effects of early adenotonsillectomy. (Funded by the National Institutes of Health; CHAT ClinicalTrials.gov number, NCT00560859.)

Full Text of Discussion...

Obstructive sleep apnea is common among children, with an estimated point prevalence of 1 to 5%.1 Important sequelae include cardiovascular, growth, cognitive, and behavioral deficits. Adenotonsillectomy, the usual first-line treatment, most often cures or ameliorates the disorder. Each year, 77% of the 530,000 tonsillectomies in the United States are performed for obstructive sleep apnea.2,3 Given 4 million births in the United States annually, approximately one in eight American children will eventually have their tonsils removed, thus suggesting a prevalence of obstructive sleep apnea during childhood as high as 10%. Despite the frequency and severity of pediatric obstructive sleep apnea, controversies exist about diagnosis, treatment, and postoperative care. Previous studies of adenotonsillectomy for obstructive sleep apnea have largely been observational. The Childhood Adenotonsillectomy Trial (CHAT) group now reports in the Journal results of a well-designed and well-executed multicenter, randomized trial of adenotonsillectomy for childhood obstructive sleep apnea.4 A total of 464 children, 5 to 9 years of age, with obstructive sleep apnea were randomly assigned to adenotonsillectomy within 1 month after randomization or to watchful waiting with supportive care and reevaluation for adenotonsillectomy after 7 months. The primary outcome, a measure of attention and executive function, was not significantly different across the two study groups. However, as compared with

the watchful-waiting group, the early-adenotonsillectomy group had significant improvement on polysomnographic, behavioral, symptomatic, and quality-of-life measures. Although 79% of the children in the early-adenotonsillectomy group had a normalization of polysomnographic findings after treatment, we are not told whether the other children in that group also had improvement or how many of them required additional treatment. Although 46% of the patients in the watchful-waiting group had a normalization of polysomnographic findings after 7 months, 71% were still considered by the otolaryngologist to be candidates for adenotonsillectomy. Notwithstanding the failure to show an improvement in the primary outcome, it remains possible that months to years of untreated obstructive sleep apnea can impair attention and executive function in children. The primary outcome may not have captured the disordered function, the 7-month follow-up period may have been too short, or such outcomes may be seen only in younger children or in those with more severe disease. Interestingly, a secondary outcome measure of real-world executive function did show betweengroup differences favoring early surgery. About half the children were black and approximately one third were obese two groups that have a higher prevalence of obstructive sleep apnea, as compared with children of other races or children who are nonobese.5 Subgroup analyses suggested that adenotonsillectomy was effective both in black children and in obese children. The age group studied is somewhat older than the average child with uncomplicated obstructive sleep apnea due to adenotonsillar hypertrophy. The investigators chose to study school-age children, for whom neurocognitive and behavioral measures are better established than they are for preschool children. Caution will be required when extrapolating the results to younger children, who are at different developmental stages. For clinicians faced with the decision whether to perform adenotonsillectomy, the severity of obstructive sleep apnea is an important concern. They may ask whether a given child has a serious enough problem to justify surgery. In this study, baseline severity was heterogeneous, with 25% of the patients having fewer than three obstructive events per hour of sleep (mild), 50% having three to nine events per hour (moderate), and 25% having more than nine events per hour (severe). It would be surprising if outcomes were similar across this wide range of severity. Future studies should use a similar randomized-trial design that targets children 2 to 6 years of age who have adenotonsillar hypertrophy and moderately severe obstructive sleep apnea. Two recent studies reporting mortality after tonsillectomy will undoubtedly refocus our thinking about the riskbenefit ratio for adenotonsillectomy in children.6,7 Surprisingly, in these studies, most deaths occurred not from tonsillar-bed hemorrhage but from presumed sleep apnea at home or in another unmonitored setting. Criteria for an overnight hospital stay in a monitored environment and appropriate narcotic use are discussed.6,7 Finally, I want to highlight the need for consensus across sleep, pediatric, otolaryngology, and anesthesiology specialties regarding preoperative testing for possible obstructive sleep apnea. Guidelines vary according to specialty, but it is clear that polysomnography is unavailable for many symptomatic children.8,9 I favor the use of pulse oximetry with the McGill Oximetry Score as an abbreviated testing method. This method has a high positive predictive value, grades the severity of obstructive sleep apnea, and guides perioperative management but misses children with mild obstructive sleep apnea who do not have repetitive oxygen desaturation.10,11

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BACKGROUND
A common promoter polymorphism (rs35705950) in MUC5B, the gene encoding mucin 5B, is associated with idiopathic pulmonary fibrosis. It is not known whether this polymorphism is associated with interstitial lung disease in the general population.

Full Text of Background...

METHODS
We performed a blinded assessment of interstitial lung abnormalities detected in 2633 participants in the Framingham Heart Study by means of volumetric chest computed tomography (CT). We evaluated the relationship between the abnormalities and the genotype at the rs35705950 locus.

Full Text of Methods...

RESULTS
Of the 2633 chest CT scans that were evaluated, interstitial lung abnormalities were present in 177 (7%). Participants with such abnormalities were more likely to have shortness of breath and chronic cough and reduced measures of total lung and diffusion capacity, as compared with participants without such abnormalities. After adjustment for covariates, for each copy of the minor rs35705950 allele, the odds of interstitial lung abnormalities were 2.8 times greater (95% confidence interval [CI], 2.0 to 3.9; P<0.001), and the odds of definite CT evidence of pulmonary fibrosis were 6.3 times greater (95% CI, 3.1 to 12.7; P<0.001). Although the evidence of an association between the MUC5B genotype and interstitial lung abnormalities was greater among participants who were older than 50 years of age, a history of cigarette smoking did not appear to influence the association.

Full Text of Results...

CONCLUSIONS
The MUC5B promoter polymorphism was found to be associated with interstitial lung disease in the general population. Although this association was more apparent in older persons, it did not appear to be influenced by cigarette smoking. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number,NCT00005121.)

Bedside to Gene and Back in Idiopathic Pulmonary Fibrosis

William O.C. Cookson, M.D., D.Phil., and Miriam F. Moffatt, D.Phil. May 21, 2013DOI: 10.1056/NEJMe1304758 Share: Article References

Idiopathic pulmonary fibrosis is a syndrome of chronic, progressive fibrosing interstitial pneumonia of unknown cause.1 The prevalence of this disorder, which is associated with a rate of death

similar to that of lung cancer, is increasing.2 The only consistent clues to its cause have been that it occurs primarily in older adults, many of whom have been smokers. As has been the case for other mysterious illnesses, genetic studies have resulted in an improved understanding of this disorder. Mutations in genes encoding surfactant proteins C and A2 (SFTPCand SFTPA2, respectively), telomerase reverse transcriptase (TERT), and telomerase RNA component (TERC) were initially discovered in cases of rare familial idiopathic pulmonary fibrosis.3Two years ago, Seibold et al.4 identified a genetic linkage and association with a cluster of gel-forming mucin genes on chromosome 11p. Their finding of a strong association with a singlenucleotide polymorphism (SNP), rs35705950, located 3 kb upstream of MUC5B, has been robustly replicated. The minor allele of rs35705950 conferred a high odds ratio for idiopathic pulmonary fibrosis (9.0 for heterozygotes and 21.8 for homozygotes) and was associated with increased lung expression of MUC5B. These loci and others with as yet less clear attributions to particular genes have been recently identified in a genomewide association study.5 Hunninghake and colleagues6 now report, in the Journal, on whether rs35705950 was related to abnormalities that were seen on chest computed tomography (CT) in a general population sample from the Framingham Heart Study. They identified interstitial lung abnormalities in 7% of the sample. These abnormalities were not benign, since 50% of the participants who had such abnormalities had reduced lung volumes. In participants with interstitial lung abnormalities, the odds of having each copy of the minor rs35705950 allele were increased by a factor of 2.8, with a frequency of 10.5% for the minor allele in the population. About one quarter of the participants with interstitial lung abnormalities had CT abnormalities that were diagnostic of pulmonary fibrosis, and in these participants the odds of having each copy of the minor rs35705950 allele were increased by a factor of 6.3. Although the effects of age and cigarette smoking were below the threshold for statistical proof, it is in keeping with previous results that the odds ratios for interstitial lung abnormalities were higher in participants older than 50 years of age and in those who were current or past smokers. Interstitial pneumonias in patients with systemic sclerosis do not show an association with rs35705950.7 Conversely, mutations in TERT and TERC are associated with systemic manifestations in the skin and bone marrow, findings that suggest the presence of systemic and local syndromes of interstitial pneumonia with differing causes. For the past 20 years, most research into idiopathic pulmonary fibrosis has been directed at the cellular and signaling events that drive fibrosis. The results reported in the Journal 4,6 prompt a rethinking about the disorder, since they suggest the presence of a spectrum of fibrotic diseases in which secreted mucins play a major role. The known role of mucins in providing an effective mucosal barrier, the contribution of surfactant mutations to familial idiopathic pulmonary fibrosis, the effects of cigarette smoking, and the observation that idiopathic pulmonary fibrosis is confined to the lung1 all suggest an important environmental component to the disease. The high penetrance of the MUC5B susceptibility allele suggests that any environmental factor is likely to be common. Idiopathic pulmonary fibrosis has histopathological similarities to those of asbestosis,8 and Hunninghake et al. identified five possible cases of asbestos exposure (on the basis of the presence of pleural plaques) in the participants, two of whom carried the rs35705950

risk allele. Although pneumoconiosis is no longer a common cause of pulmonary fibrosis, the parallel with asbestosis suggests that novel environmental factors may reach the alveoli. The results suggest that identification of the putative environmental factor or factors should be a priority for research into idiopathic pulmonary fibrosis. Chronic occult infections bacterial, fungal, or viral must be high on the list of suspects. A hypothesis for a bacterial component to the disease is supported by a recent study showing that high-dose, protracted courses of trimethoprimsulfamethoxazole reduce mortality from idiopathic pulmonary fibrosis,9 whereas immunosuppression may increase the risk of death and hospitalization. 10 It is fashionable to decry genetic studies as dull and stereotyped, but to do them as effectively as the investigations of idiopathic pulmonary fibrosis reported in the Journal is demanding and difficult. These results are an exemplar of the robust foundations that genetic studies can provide to the understanding of complex diseases.
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Illness and death from cystic fibrosis are due primarily to progressively destructive lung disease resulting in bronchiectasis and respiratory failure. Computed tomography (CT) can detect changes in the lungs associated with bronchiectasis1,2 and evidence of structural lung disease in children with cystic fibrosis as young as 10 weeks of age.3-8 The true prevalence of bronchiectasis among children with cystic fibrosis is unknown; however, studies conducted by the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) and the Australasian Cystic Fibrosis Bronchoalveolar Lavage study group have shown that 50 to 70% of patients have CT-defined bronchiectasis by 3 to 5 years of age.3,5,9 Once present, bronchiectasis persists and progresses in approximately 75% of young children,3 despite receipt of the best current therapy. A coordinated approach to early surveillance in young children with cystic fibrosis has been developed by the AREST CF, a collaborative program of the pediatric cystic fibrosis clinics at Princess Margaret Hospital for Children, Perth, and the Royal Children's Hospital, Melbourne. The clinics serve the entire populations of Western Australia and Victoria, respectively, apart from the southern metropolitan region of Melbourne. The program includes assessments soon after diagnosis (average age, 3 months) and annually until 6 years of age, encompassing clinical assessment, lung-function testing, chest CT with the use of a low-radiation protocol, bronchoalveolar lavage (BAL), and collection of blood and urine samples (see the Supplementary

Appendix, available with the full text of this article at NEJM.org).

Previous studies from the AREST CF, using largely cross-sectional data, have shown that neutrophilic inflammation (characterized by the presence of free neutrophil elastase activity in BAL fluid) and pulmonary infection (especially with Pseudomonas aeruginosa) are the major risk factors for early disease in cystic fibrosis, including the development and progression of bronchiectasis,3-5a reduction in the body-mass index,10 and lung-function decline.11 BAL-based studies have shown that lung disease begins early in life46,12,13 and is associated with increased levels of proinflammatory cytokines, such as CXCL8 (interleukin-

8),4,14 and that more extensive inflammation is found in lung lobes with more severe bronchiectasis.6 We conducted the current study to test the hypothesis that the risk of bronchiectasis, especially persistent bronchiectasis, could be accurately determined by measuring biomarkers of inflammation and infection in BAL fluid at 3 months of age.

METHODS
Study Population We examined data from 127 consecutive infants who received a diagnosis of cystic fibrosis on the basis of newborn screening and who were participants in the AREST CF surveillance program. Assessments were undertaken when the children were in stable clinical condition. We sought to determine whether pulmonary inflammation and infection detected in BAL fluid at 3 months and 1, 2, and 3 years of age were associated with the development of bronchiectasis by 3 years of age. CT and BAL Chest CT and BAL were performed while the infants were under general anesthesia.3-5 Children were initially intubated with a cuffed tracheal tube; a standardized recruitment maneuver, consisting of 10 consecutive slow breaths up to total lung capacity (transrespiratory pressure [PRS], 37 to 40 cm of water) over a positive end-expiratory pressure of 5 cm of water for 1 to 2 seconds after each inspiration, was used to reduce procedure-related atelectasis. A volume-controlled, limited-slice CT scan (initial scan at 3 months of age; see Table S1 in the Supplementary Appendix) was obtained, with three slices obtained at both end inspiration (PRS, 25 cm of water) and end expiration (PRS, 0 cm of water); a volume-controlled volumetric CT scan was obtained at end inspiration for older children (starting in 2007 in Perth and 2010 in Melbourne). Details of the scanners and settings used have been published previously.3,15 CT images were scored, as previously reported, with no knowledge of the child's clinical status or the results of any previous scans or tests to detect infection or inflammation.3-5 Each scan was considered in six zones (upper, middle, and lower areas of the left and right lungs), and each zone was scored for the presence or absence and extent of bronchiectasis (on inspiratory scans) and gas trapping (on expiratory scans). Bronchiectasis was defined as a bronchus-to-artery ratio of more than 1.0 or the presence of a nontapering bronchus in the transverse plane.3,5 To avoid overinterpretation of radiologically defined disease, especially from limited-slice scans in early life, we defined persistent bronchiectasis as bronchiectasis that was present on two successive scans, scored independently. This assessment was performed at 12 months and 3 years of age. BAL was performed after CT, with the tracheal tube replaced by a laryngeal mask airway for passage of the bronchoscope. The right middle lobe was lavaged with three aliquots of warmed normal saline (1 ml per kilogram of body weight), with one additional aliquot lavaged into the lingua or the most affected lobe identified on CT. Pulmonary Inflammation and Infection The first aliquot from each lobe was processed for detection of bacteria, viruses, or fungi.4Pulmonary infection was determined as previously described,16 with infection defined as a colony count for a specific organism (excluding mixed oral flora) of 105 colony-forming units per milliliter or more. In the case of P.

aeruginosa, however, the criterion for infection was the presence of the organism in any density in BAL
cultures. The second and third aliquots retrieved from the right middle lobe were pooled and used for analyses of inflammation, as previously described.4 Total and differential cell counts were performed and free neutrophil elastase activity was determined; the lower limit of detection for neutrophil elastase activity was 200 ng per milliliter.4 Statistical Analysis Logistic regression was performed to determine cross-sectional associations between inflammatory and infection variables assessed by means of BAL and the presence of bronchiectasis at 3 months of age.

Longitudinal analyses were performed to determine the associations between inflammatory and infection variables and the presence or absence of bronchiectasis from 3 months to 3 years of age. Generalized estimating equations were used for up to four repeated measurements in each child. We assumed a binomial family, logit link, and first-order autoregressive correlation structure. We tested the significance of the interaction between each inflammatory and infection variable and the age at the time of the scan by adding the interaction term to a model containing both main effects and comparing it with the model containing only the main effects. In the absence of significant interactions, each variable of interest was examined univariately, and variables that were significant at the 0.20 level were included in a multivariable model. Variables were retained in the multivariable model if they were significant at the 0.05 level. Analyses were performed separately with bronchiectasis as the outcome and with persistent bronchiectasis as the outcome. The association between the presence of persistent bronchiectasis at 12 months and at 3 years of age and data collected at 3 months of age was examined with the use of logistic regression. Further details of the analyses and the data sets used are shown in Table S1 in the Supplementary Appendix.

RESULTS
Characteristics of the Study Participants Longitudinal data were available from 3 months of age for 127 children with cystic fibrosis, with 127 assessed at a mean (SD) age of 0.350.12 years, 109 assessed at 1.170.20 years, 92 assessed at 2.170.23 years, and 81 assessed at 3.200.22 years. The primary reason for the smaller numbers of children with increasing age was that the children had not yet reached the assessment age by the end of

the data-collection period (Figure 1FIGURE 1

Children Included in the Analyses at 3, 12,

24, and 36 Months.). Demographic and clinical data are shown in Table 1TABLE 1 Demographic and Clinical Characteristics of the Study Population, According to Time of Assessment.. The point

prevalence of bronchiectasis increased from 29.3% at 3 months of age to 61.5% at 3 years of age (P<0.001) (Table 1). The cumulative prevalence of bronchiectasis reached 83.7% by 3 years of age. The point prevalence of CT-defined gas trapping at each visit was 68.0% at 3 months, 68.5% at 1 year, 71.6% at 2 years, and 69.2% at 3 years (Table 1). At the initial assessment, at 3 months of age, 28 of 120 children (23.3%) had detectable neutrophil elastase activity in BAL fluid, and 36 of 123 (29.3%) had bronchiectasis on the chest CT scan. Demographic and clinical data stratified according to status with respect to neutrophil elastase activity and bronchiectasis at

the initial assessment are shown in Table 2TABLE 2

Characteristics of the Study

Participants at the 3-Month Assessment, According to Status with Respect to Neutrophil Elastase Activity and Bronchiectasis at That Time.. Neutrophil elastase activity in BAL fluid was associated with the presence of

respiratory symptoms at the time of BAL (P=0.007), pancreatic insufficiency (P=0.006), and pulmonary infection (P=0.02). Bronchiectasis on the initial CT scan was associated with respiratory symptoms (P=0.01), meconium ileus at presentation (P=0.002), and any pulmonary infection (P=0.03) or infection with P. aeruginosa (P=0.02) (Table 2). Risk Factors for Bronchiectasis Risk factors associated with the development of bronchiectasis from 3 months to 3 years of age are shown

in Table 3TABLE 3

Longitudinal Analyses of Risk Factors for Bronchiectasis from 3 Months to 3

Years of Age.. Risk factors for bronchiectasis on multivariate analysis were meconium ileus at presentation

(odds ratio, 3.17; 95% confidence interval [CI], 1.51 to 6.66; P=0.002), respiratory symptoms at the time of CT and BAL (odds ratio, 2.27; 95% CI, 1.24 to 4.14; P=0.008), neutrophil elastase activity in BAL fluid (odds ratio, 3.02; 95% CI, 1.70 to 5.35; P<0.001), and gas trapping on expiratory CT (odds ratio, 2.05; 95% CI, 1.17 to 3.59; P=0.01). There were no significant interactions between any of the risk factors and the age at which BAL was performed. A sensitivity analysis, with the assumption that once bronchiectasis was detected, all subsequent scans would be positive, had similar results (Table S2 in the Supplementary

Appendix), with the presence of neutrophil elastase activity in BAL fluid and initial presentation with
meconium ileus as significant predictors in multivariate analyses. Risk Factors for Persistent Bronchiectasis Persistent bronchiectasis was observed in 15 of 104 children (14.4%) at 12 months of age and in 25 of 78 children (32.1%) at 3 years of age. Risk factors for persistent bronchiectasis at these ages are shown

in Table 4TABLE 4

Risk Factors at 3 Months for Persistent Bronchiectasis at 12 Months of Age and

at 3 Years of Age.. Neutrophil elastase activity in BAL fluid at 3 months of age was the major predictor of

persistent bronchiectasis at both 12 months of age (odds ratio, 7.20; 95% CI, 2.14 to 24.28; P<0.001) and 3 years of age (odds ratio, 4.21; 95% CI, 1.45 to 12.21; P=0.008).

DISCUSSION
Bronchiectasis develops early in infants with cystic fibrosis. In our study, risk factors at 3 months of age for detection of bronchiectasis included meconium ileus on presentation, respiratory symptoms, pulmonary infection (especially with P. aeruginosa), and gas trapping on the CT scan. Free neutrophil elastase activity in BAL fluid at 3 months of age was associated with increased odds of persistent bronchiectasis; the odds were seven times as high at 12 months of age and four times as high at 3 years of age. The results of this longitudinal study are consistent with those of our previous studies, which showed that free neutrophil elastase activity in BAL fluid and pulmonary infection were risk factors for both the

development and progression of bronchiectasis.3-5 What this study adds is evidence that free neutrophil elastase activity at 3 months of age increases the odds of persistent bronchiectasis at both 12 months and 3 years of age. Gas trapping on expiratory CT was also a risk factor for bronchiectasis, and although this may represent early-onset peripheral lung disease, the precise relationship between gas trapping and bronchiectasis requires clarification. Cystic fibrosis is characterized by extensive and chronic neutrophilic inflammation of the airways. Neutrophils play a major part in antibacterial defense through the release and activation of enzymes, including peroxidases (e.g., myeloperoxidase) and proteases (including neutrophil elastase).17,18The primary lung defense against neutrophil elastase is 1-antitrypsin,17 which binds extracellular neutrophil elastase. Bound neutrophil elastase cannot digest elastin. Extracellular or surface-associated neutrophil elastase19 that exceeds antiprotease-binding capacity will be active and capable of elastin digestion, which is presumed to underlie the development of bronchiectasis. The presence of free neutrophil elastase activity in the lung is associated with active neutrophilic inflammation and, although such activity was seen in a minority of children at each BAL performed in this study (Table 1), it is a potent risk factor for bronchiectasis. Several limitations of this study need to be acknowledged. In the AREST CF program, chest CT and BAL are performed when the child is in stable clinical condition and is fit for anesthesia. Thus, we cannot comment on the role of respiratory viral infections in the development of bronchiectasis. In addition, our data do not reflect the situation during an acute respiratory exacerbation, when viral and bacterial infections are more likely to be found.9 Finally, there is controversy about whether early radiologic detection of dilated airways represents the onset of the destructive process resulting in bronchiectasis. We have reported that when CT scans are obtained 12 months apart, dilatation of the airways persists on the later scan in approximately 75% of children.3 In the present study, 31 children had apparent resolution of bronchiectasis (Table S1 in the Supplementary Appendix). This could be a particular problem in interpreting dilated airways on limited-slice scans obtained at an early age. To overcome this limitation, we have introduced the term persistent bronchiectasis for the detection of dilated airways on two or more sequential scans. In addition, we have conservatively defined dilated airways as those with a bronchus-toartery ratio of more than 1.0.3-5 Kapur et al.20reported a mean ratio of 0.63 (95% CI, 0.60 to 0.65) in 41 children without apparent pulmonary pathologic features and suggested that a ratio of more than 1.0 underestimates the prevalence of early disease. Thus, the prevalence of bronchiectasis in our study may underestimate the true prevalence. The AREST CF surveillance program has practical limitations; it provides a once-a-year snapshot, arguably not at the most informative time. Our data do suggest that noninvasive or minimally invasive assessment of activated neutrophils is needed to show the true role of pulmonary free neutrophil elastase activity in the development and persistence of bronchiectasis. Unfortunately, such biomarkers have not been studied in infants with cystic fibrosis. Potential biomarkers studied in adults and older children include urinary desmosines,21 1-antitrypsin:CD16b complex,22 and YKL-40.23 None of them have been validated in infants or in early disease. Data from the present study suggest that treatment that targets activated neutrophils or that inhibits neutrophil elastase activity could be a logical strategy for preventing bronchiectasis. Such therapies are available or are under investigation in clinical trials,24-26 highlighting the relevance of understanding the

role that neutrophil elastase may play in disease initiation and progression. Studies of ibuprofen in older children and adults have shown a delayed decrease in lung function and improved maintenance of weight, with these findings attributed to antiinflammatory activity.27,28However, ibuprofen is not used widely and has not been tested in appropriate trials involving infants. Our data showing the association of free neutrophil elastase activity in BAL fluid at 3 months of age with persistent bronchiectasis at both 12 months and 3 years of age suggest that free neutrophil activity could be used as a criterion to select high-risk infants for clinical trials. The antiinflammatory properties of neutrophil elastase inhibitors are well established,26 and at least one such agent has shown promise in early trials involving adults with cystic fibrosis.24 In conclusion, free neutrophil elastase activity in the lung at 3 months of age was associated with increased odds of persistent bronchiectasis at 12 months and at 3 years of age. This observation sets the stage for trials of treatments that target activated neutrophils or inhibit neutrophil elastase activity in order to prevent or delay the onset of bronchiectasis in patients with cystic fibrosis.

SUNDAY, April 14 (HealthDay News) -- For the first time, scientists have been able to bioengineer an animal kidney and see it work in a living animal, in what they hope is a step toward creating organs for people with failing kidneys. A kidney transplant is the only cure for people with advanced kidney failure, but there aren't enough donor organs to meet the need. In the United States, nearly 1 million people have end-stage kidney disease, and there are currently more than 95,000 on the waiting list for a donor organ, according to data from the United Network for Organ Sharing. In the new study, researchers at Harvard and Massachusetts General Hospital created a replacement kidney that, when transplanted into rats, immediately began producing urine as a normal kidney would. The artificial organ could not match the full function of a normal kidney, but experts said the findings are a promising step toward creating replacement kidneys for people. "These results are really quite impressive," said Dr. Mala Sachdeva, a kidney specialist who was not involved in the research. "The transplanted tissue was actually functional." The findings, released early online April 14 by the journal Nature Medicine, "offer great promise," said Sachdeva, a nephrologist at North Shore University Hospital Transplant Center in Manhasset, N.Y. However, she stressed, "it's very early to get our hopes up too high. A lot more work needs to be done." Senior researcher Dr. Harald Ott agreed that years of study remain. "This study really just shows a proof of principle," said Ott, of Harvard Medical School and the Center for Regenerative Medicine at Massachusetts General Hospital. In an "ideal world," Ott said, scientists would someday be able to create new kidneys "on demand" from kidney failure patients' own body cells. That could potentially not only ease donor organ shortages, but also address the problem of organ rejection, both Ott and Sachdeva said.

Right now, doctors try to find donor kidneys that match a patient's genetic profile as closely as possible. Even so, transplant recipients have to remain on drugs that suppress the immune system, to lower the likelihood of an immune system attack on the foreign organ. And those drugs, Sachdeva noted, come with side effects -- including a higher susceptibility to infections or, over time, cancer. Some immunosuppressants can cause conditions such as bone disease, high blood pressure or cataracts. Finding a way to create kidneys from patients' own cells could limit the need for those drugs, according to Ott. But first, the researchers have to figure out how to "scale up" this technology to humans, he said. Ott's team engineered the replacement kidneys by first stripping rat kidneys of their "living cells," using a detergent solution. That left behind a collagen "scaffold" that the researchers repopulated with kidney cells from newborn rats, as well as human cells that were used to replace the lining of the kidney blood vessels. The organs were then cultured in the lab before being transplanted into rats that had one kidney removed. Ott's team found that the engineered kidneys were able to produce urine. There are still plenty of questions about how this would be translated to humans, according to Ott. One is, where would the kidney "scaffolds" come from? You could use kidneys from cadavers, Ott said -but then there would still be a need for donor organs. It's also unclear if a patient's immune system would react against the foreign scaffold, even with his or her own cells repopulating it. Ott's team has already found that human and pig kidneys can be stripped of their cells to form a scaffold. It's possible, Ott said, that pig kidneys could be used to form the scaffold for human replacement kidneys. There's also the question of what cell types from patients would work. Can patients' blood cells, for instance, be coaxed into becoming mature kidney cells? Ott said it's hard to estimate how long it will take to answer those questions. "But if this technology works out, clinical application will be years away," he said. Still, he added, "I think there's room for cautious optimism." SOURCES: Harald Ott, M.D., Center for Regenerative Medicine, Massachusetts General Hospital, Boston; Mala Sachdeva, M.D., assistant professor, medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, N.Y.; April 14, 201

The National Lung Screening Trial showed that three rounds of low-dose CT scan screening could reduce lung cancer mortality by at least 20%. The selection criteria for screening were 30 pack-years of smoking and <15 years since quitting for those who have quit. Taking into account additional risk factors, including ethnic group, level of education, body mass index, presence of chronic obstructive pulmonary disease, personal history of cancer, family history of lung cancer, and smoking intensity (average number of cigarettes smoked each day), and then applying the new model to the National Lung Screening Trial results, it appears that the new risk model would have missed 41% fewer cancers and increased the positive predictive value from 3.4% to 4%,

without increasing the rate of false negatives significantly (Tammemgi et al., 2013). The hope is that refinement in the criteria for selecting subjects for screening will save more lives with fewer investigations for lesions that are not lung cancer.

MONDAY, May 20 (HealthDay News) -- Obese and overweight men and women who suffer from heartburn often report relief when they lose weight, a new study shows. The researchers tracked the effects of weight loss over a year in patients who had a persistent form of heartburn known as gastroesophageal reflux, or GERD. "If you lose weight, you will have improvements in your reflux symptoms," said study author Dr. Preetika Sinh, a gastroenterology fellow at the University of Kansas School of Medicine. In women, but not men, long-term exercise also helped reduce symptoms, she added. Sinh was scheduled to present the findings Monday at the Digestive Disease Week annual meeting in Orlando, Fla. Previous research also has linked weight loss with a decline in GERD symptoms. Heartburn, or acid indigestion, is very common, with more than 60 million Americans having it at least once a month, according to the American College of Gastroenterology. Stomach acid flows backward up into the esophagus, and the burn begins. GERD, the more frequent, chronic form of heartburn, can lead to complications if left untreated, including a narrowing of the esophagus or precancerous changes in the esophageal lining. Sinh evaluated more than 200 men and women with an average age of 46. At the start of the study, all were overweight or obese, with an average weight of 220 pounds. At the beginning of the study, 38 percent had heartburn scores severe enough to be classified as GERD. After six months, the patients' average weight decreased to 183 pounds, and only 16 percent still had GERD. During the next six months, 172 of the patients regained weight, and the percentage of those with heartburn increased again, from 16 percent to 22 percent. Even a small amount of weight gain -- less than 5 percent of their initial weight -- led to worsening symptoms, Sinh found. Sinh then focused on the 41 patients who didn't regain their weight and found that the percentage with heartburn continued to decline and the symptoms continued to improve. As part of the weight-loss program, the patients were told to aim for five hours a week of moderate activity such as walking or jogging. The average amount logged was a little less than four hours, Sinh said. In women, but not men, the exercise also helped to improve heartburn. Sinh said she can't explain the mechanisms behind either the weight loss or the exercise, or why the exercise seemed to help only women. Although the study found a link between weight loss, exercise and GERD, it did not establish a cause-and-effect relationship.

While the use of heartburn medications is common, Sinh said she can't say if the men and women improved enough to go off medication, since she didn't track those results. Only about 5 percent of the men and women were on heartburn medications in the first place, she said. One expert said the study had some strengths. To start with, a relatively large number of people were studied, said Dr. Lauren Gerson, an associate professor of medicine and gastroenterology at Stanford University School of Medicine. Besides just asking patients to report symptoms, she said, "it would be useful to have pH studies [done to evaluate GERD] to document improvement in overall pH scores after weight loss." Even so, she said, the findings echo those of an even larger study, published in 2006, that found that weight gain -- even in those with normal weight -- was linked to new heartburn symptoms and weight reduction was linked to a decline in symptoms. Whether weight loss can help those with heartburn discontinue reflux medications remains an unanswered question, Gerson said. Because this study was presented at a medical meeting, the data and conclusions should be viewed as preliminary until published in a peer-reviewed journal. SOURCES: Preetika Sinh, M.D., gastroenterology fellow, Universit

Rponse : Huit Il faut chercher tout d'abord les ondes P sinusales, puis les ondes P prmatures et lgrement diffrentes de l'onde P. A noter ici trois QRS aberrants (bloc intraventriculaire frquence-dpendant). Extrasystole auriculaire

Activit auriculaire prmature, non sinusale, originaire de loreillette droite ou gauche. Linflux dpolarise le muscle auriculaire de proche en proche et descend habituellement par voie antrograde, via le nud AV et le faisceau de His, vers les ventricules. Les ESA sont frquentes et bnignes chez le sujet sain. Leur incidence augment e avec lge ; elles sont quasi constantes au-del de 60 ans. Si elles surviennent sur cardiopathie ou si elles sont polymorphes et couplage court, elles exposent une arythmie auriculaire en salves ou soutenue ( tachycardie atriale, flutter etfibrillation auriculaire). Sur lECG, on observe un auriculogramme prmatur, non sinusal (onde P). Londe P est de morphologie diffrente de londe P sinusale, sauf si elle nat proximit du nud sinusal. Lintervalle P-R est lintervalle P-R en rythme sinusal ou plus court si lESA nat dans loreillette droite basse ou prs du sinus coronaire. Le complexe QRS conduit est gnralement identique aux QRS de base. Certaines ESA conduites prcocement peuvent entraner un bloc AV partiel (PR long) ou complet (onde P bloque) si elles arrivent dans le nud AV au cours de sa priode rfractaire. Elles peuvent aussi entraner un bloc de branche par un phnomne daberration ventriculaire. Certaines ESA surviennent de faon rgulire tous les deux ou trois complexes P-QRS ; on parle dESA bigmines ou trigmines. Lorsque le couplage est variable, quil y a une fusion et/ou que les intervalles interectopiques ont un dnominateur commun, il faut voquer une parasystolie.

Les ESA pntrent et recyclent habituellement le nud sinusal, aussi la somme des intervalles pr- et post-extrasystolique est infrieure au double de lintervalle P -P sinusal normal.

ACKGROUND
Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear.

METHODS
We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either wholegenome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis.

RESULTS
AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylationrelated genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories.

CONCLUSIONS
We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this

study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.)