Domination based classification algorithms for the controllability analysis of biological interaction networks.

Deciding the size of a minimum dominating set is a classic NP-complete problem. It has found increasing utility as the basis for classifying vertices in networks derived from protein-protein, noncoding RNA, metabolic, and other biological interaction data. In this context it can be helpful, for example, to identify those vertices that must be present in any minimum solution. Current classification methods, however, can require solving as many instances as there are vertices, rendering them computationally prohibitive in many applications. In an effort to address this shortcoming, new classification algorithms are derived and tested for efficiency and effectiveness. Results of performance comparisons on real-world biological networks are reported.

Molecular Subtyping and Outlier Detection in Human Disease Using the Paraclique Algorithm.

Recent discoveries of distinct molecular subtypes have led to remarkable advances in treatment for a variety of diseases. While subtyping via unsupervised clustering has received a great deal of interest, most methods rely on basic statistical or machine learning methods. At the same time, techniques based on graph clustering, particularly clique-based strategies, have been successfully used to identify disease biomarkers and gene networks. A graph theoretical approach based on the paraclique algorithm is described that can easily be employed to identify putative disease subtypes and serve as an aid in outlier detection as well. The feasibility and potential effectiveness of this method is demonstrated on publicly available gene co-expression data derived from patient samples covering twelve different disease families.

MicroRNA Profiling in Adipose Before and After Weight Loss Highlights the Role of miR-223-3p and the NLRP3 Inflammasome.

OBJECTIVE: Adipose tissue plays a key role in obesity-related metabolic dysfunction. MicroRNA (miRNA) are gene regulatory molecules involved in intercellular and inter-organ communication. It was hypothesized that miRNA levels in adipose tissue would change after gastric bypass surgery and that this would provide insights into their role in obesity-induced metabolic dysregulation. METHODS: miRNA profiling (Affymetrix GeneChip miRNA 2.0 Array) of omental and subcutaneous adipose (n = 15 females) before and after gastric bypass surgery was performed. RESULTS: One omental and thirteen subcutaneous adipose miRNAs were significantly differentially expressed after gastric bypass, including downregulation of miR-223-3p and its antisense relative miR-223-5p in both adipose tissues. mRNA levels of miR-223-3p targets NLRP3 and GLUT4 were decreased and increased, respectively, following gastric bypass in both adipose tissues. Significantly more NLRP3 protein was observed in omental adipose after gastric bypass (P = 0.02). Significant hypomethlyation of NLRP3 and hypermethylation of miR-223 were observed in both adipose tissues after gastric bypass. In subcutaneous adipose, significant correlations were observed between both miR-223-3p and miR-223-5p and glucose and between NLRP3 mRNA and protein levels and blood lipids. CONCLUSIONS: This is the first report detailing genome-wide miRNA profiling of omental adipose before and after gastric bypass, and it further highlights the association of miR-223-3p and the NLRP3 inflammasome with obesity.

Genome-wide DNA methylation analysis reveals loci that distinguish different types of adipose tissue in obese individuals.

BACKGROUND: Epigenetic mechanisms provide an interface between environmental factors and the genome and are known to play a role in complex diseases such as obesity. These mechanisms, including DNA methylation, influence the regulation of development, differentiation and the establishment of cellular identity. Here we employ two approaches to identify differential methylation between two white adipose tissue depots in obese individuals before and after gastric bypass and significant weight loss. We analyse genome-wide DNA methylation data using (a) traditional paired t tests to identify significantly differentially methylated loci (Bonferroni-adjusted P ≤ 1 × 10-7) and (b) novel combinatorial algorithms to identify loci that differentiate between tissue types. RESULTS: Significant differential methylation was observed for 3239 and 7722 CpG sites, including 784 and 1129 extended regions, between adipose tissue types before and after significant weight loss, respectively. The vast majority of these extended differentially methylated regions (702) were consistent across both time points and enriched for genes with a role in transcriptional regulation and/or development (e.g. homeobox genes). Other differentially methylated loci were only observed at one time point and thus potentially highlight genes important to adipose tissue dysfunction observed in obesity. Strong correlations (r > 0.75, P ≤ 0.001) were observed between changes in DNA methylation (subcutaneous adipose vs omentum) and changes in clinical trait, in particular for CpG sites within PITX2 and fasting glucose and four CpG sites within ISL2 and HDL. A single CpG site (cg00838040, ATP2C2) gave strong tissue separation, with validation in independent subcutaneous (n = 681) and omental (n = 33) adipose samples. CONCLUSIONS: This is the first study to report a genome-wide DNA methylome comparison of subcutaneous abdominal and omental adipose before and after weight loss. The combinatorial approach we utilised is a powerful tool for the identification of methylation loci that strongly differentiate between these tissues. This study provides a solid basis for future research focused on the development of adipose tissue and its potential dysfunction in obesity, as well as the role DNA methylation plays in these processes.

Lower Bounds on Paraclique Density.

The scientific literature teems with clique-centric clustering strategies. In this paper we analyze one such method, the paraclique algorithm. Paraclique has found practical utility in a variety of application domains, and has been successfully employed to reduce the effects of noise. Nevertheless, its formal analysis and worst-case guarantees have remained elusive. We address this issue by deriving a series of lower bounds on paraclique densities.

Maternal conditions and perinatal characteristics associated with autism spectrum disorder and intellectual disability.

BACKGROUND: As well as being highly comorbid conditions, autism spectrum disorders (ASD) and intellectual disability (ID) share a number of clinically-relevant phenomena. This raises questions about similarities and overlap in diagnosis and aetiological pathways that may exist for both conditions. AIMS: To examine maternal conditions and perinatal factors for children diagnosed with an ASD, with or without ID, and children with ID of unknown cause, compared with unaffected children. METHODS: The study population comprised all live singleton births in Western Australia (WA) between January 1984 and December 1999 (N = 383,153). Univariate and multivariate multinomial logistic regression models were applied using a blocked modelling approach to assess the effect of maternal conditions, sociodemographic factors, labour and delivery characteristics and neonatal outcomes. RESULTS: In univariate analyses mild-moderate ID was associated with pregnancy hypertension, asthma, urinary tract infection, some types of ante-partum haemorrhage, any type of preterm birth, elective C-sections, breech presentation, poor fetal growth and need for resuscitation at birth, with all factors showing an increased risk. Severe ID was positively associated with poor fetal growth and need for resuscitation, as well as any labour or delivery complication. In the multivariate analysis no maternal conditions or perinatal factors were associated with an increased risk of ASD without ID. However, pregnancy hypertension and small head circumference were associated with a reduced risk (OR = 0.64, 95% CI: 0.43, 0.94; OR = 0.58, 95% CI: 0.34, 0.96, respectively). For ASD with ID, threatened abortion before 20 weeks gestation and poor fetal growth were associated with an increased risk. CONCLUSION: Findings show that indicators of a poor intrauterine environment are associated with an elevated risk of ID, while for ASD, and particularly ASD without ID, the associations are much weaker. As such, these findings highlight the importance of accounting for the absence or presence of ID when examining ASD, if we are to improve our understanding of the causal pathways associated with these conditions.

One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates.

BACKGROUND: Animal studies and trials in older children and adults suggest that a one dose per day regimen of gentamicin is superior to a multiple doses per day regimen. OBJECTIVES: To compare the efficacy and safety of one dose per day compared to multiple doses per day of gentamicin in suspected or proven sepsis in neonates. SEARCH METHODS: Eligible studies were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, April 2011), MEDLINE (1966 to April 2011), EMBASE 1980 to April 2011, and CINAHL (December 1982 to April 2011). Abstracts of the Society for Pediatric Research were searched from 1980 to 2010 inclusive. SELECTION CRITERIA: All randomised or quasi randomised controlled trials comparing one dose per day ( 'once a day') compared to multiple doses per day ( 'multiple doses a day') of gentamicin to newborn infants < 28 days of life. DATA COLLECTION AND ANALYSIS: Data collection and analysis was performed according to the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: Eleven studies were included (N = 574) and nineteen excluded. All infants in both 'once a day' as well as 'multiple doses a day' regimen showed adequate clearance of sepsis [typical RD 0.00 (95% CI - 0.19 to 0.19); 3 trials; N = 36]. For the other primary outcome measures relating to gentamicin pharmacokinetics 'once a day' dosing of gentamicin was superior. 'Once a day' gentamicin regimen was associated with less failures to attain peak level of at least 5 µg/ml [typical RR 0.22 (95% CI 0.11 to 0.47); 9 trials; N = 422] and less failures to achieve trough levels of < 2 µg/ml [typical RR 0.38 (95% CI 0.27 to 0.55); 11 trials N = 503] compared to 'multiple doses a day' regimen.Ototoxicity and nephrotoxicity were not noted with either of the treatment regimens. AUTHORS' CONCLUSIONS: There is insufficient evidence from the currently available RCTs to conclude whether 'once a day' or 'multiple doses a day' regimen of gentamicin is superior in treating proven neonatal sepsis. However, data suggests that pharmacokinetic properties of 'once a day' gentamicin regimen are superior to 'multiple doses a day' regimen in that it achieves higher peak levels while avoiding toxic trough levels. There is no change in nephrotoxicity or auditory toxicity. Based on this assessment of pharmacokinetics, 'once a day regimen' may be superior in treating neonatal sepsis in neonates greater than 32 weeks gestation.

Effect of an extended midwifery postnatal support programme on the duration of breast feeding: a randomised controlled trial.

OBJECTIVE: to evaluate the effects of an extended midwifery support (EMS) programme on the proportion of women who breast feed fully to six months. DESIGN: randomised controlled trial. SETTING: large public teaching hospital in Australia. PARTICIPANTS: 849 women who had given birth to a healthy, term, singleton baby and who wished to breast feed. INTERVENTION: participants were allocated at random to EMS, in which they were offered a one-to-one postnatal educational session and weekly home visits with additional telephone contact by a midwife until their baby was six weeks old; or standard postnatal midwifery support (SMS). Participants were stratified for parity and tertiary education. MEASUREMENTS: the main outcome measures were prevalence of full and any breast feeding at six months postpartum. FINDINGS: there was no difference between the groups at six months postpartum for either full breast feeding [EMS 43.3% versus SMS 42.5%, relative risk (RR) 1.02, 95% confidence interval (CI) 0.87-1.19] or any breast feeding (EMS 63.9% versus SMS 67.9%, RR 0.94, 95%CI 0.85-1.04). CONCLUSIONS: the EMS programme did not succeed in improving breast-feeding rates in a setting where there was high initiation of breast feeding. Breast-feeding rates were high but still fell short of national goals. IMPLICATIONS FOR PRACTICE: continuing research of programmes designed to promote breast feeding is required in view of the advantages of breast feeding for all mothers and babies.

Health and retirement in Europe.

We use discrete-time hazard models with internationally comparable data from the full eight waves of the European Community Household Panel (ECHP) to study the relationship between retirement and health in nine European countries. Our results provide new evidence of the relationship of health shocks to early retirement. The pattern of results across countries reflects international differences in the incentives created by social security systems.

Patent ductus arteriosus in extremely preterm infants receiving phototherapy: does shielding the chest make a difference? A randomized, controlled trial.

BACKGROUND: Patent ductus arteriosus (PDA), a common complication in extremely preterm infants, is associated with increased mortality and morbidity. Phototherapy has been associated with PDA, and one randomized, control trial has shown that shielding of the chest may decrease the risk of PDA. AIM: To examine if chest shielding reduces the incidence and severity of PDA in extremely preterm infants. STUDY DESIGN: Randomized clinical trial of infants < 29 wk gestation (stratified into two groups: < 27 wk gestation and 27-28 wk gestation). METHODS: Following written parental consent, eligible infants were randomized to receive phototherapy, with or without a chest shield. Ductal parameters were assessed by Doppler echocardiogram in all infants prior to starting phototherapy and at 48 h after initiation, or earlier if phototherapy was discontinued. RESULTS: 54 infants were enrolled in the study. The incidence of PDA (shield 19/27 vs no shield 21/27), ductal size (1.4 vs 1.0 mm) and left atrial/aortic root (LA/Ao) ratio (1.2 vs 1.3) were similar in the two groups pre-phototherapy. There was no difference between the groups post-phototherapy in incidence (shield 12/27 vs no shield 13/27), ductal size (1.4 vs 1.5 mm) or LA/Ao ratio (1.1 vs 1.3). CONCLUSION: Chest shielding did not alter the incidence or severity of PDA in our population of extremely preterm infants.

Preventing postnatal depression in mothers of very preterm infants: a randomised controlled trial.

OBJECTIVE: To test whether a cognitive-behaviour therapy intervention program reduces the prevalence of depression during the first postnatal year in mothers of very preterm babies. DESIGN: Prospective, single blind, randomised, controlled study. SETTING: Perinatal centre in Western Australia. PARTICIPANTS: One hundred and ninety-nine out of 673 English-speaking mothers of infants admitted to the neonatal unit. INTERVENTION: A six-session cognitive-behaviour therapy intervention program provided by a research midwife between weeks two and six after birth. Women in the control group received standard care. MAIN OUTCOME MEASURES: Depression and anxiety disorders occurring in the first year assessed by a clinical psychologist at structured interview using the Schedule for Affective Disorders and Schizophrenia (SADS) at 2 weeks, 2, 6 and 12 months. RESULTS: One hundred and one women were randomised to the intervention group and 98 to the control group. Fifty-four mothers (27%) in the trial were diagnosed with minor or major depression in the 12 months following very preterm delivery, 29 (29%) in the intervention group and 25 (26%) in the control group (relative risk 1.1 [95% CI 0.80-1.5]). There were no differences in the time of onset or the duration of the episodes of depression between the groups. Overall, 74 mothers (37%) of the 199 met criteria for a diagnosis of psychological morbidity during the first year. CONCLUSIONS: Our intervention program did not alter the prevalence of depression in these mothers. Rates of depression and stress reactions are high in these mothers.

Repeated antenatal corticosteroids: effects on cerebral palsy and childhood behavior.

OBJECTIVE: This study was undertaken to determine the effects of repeated courses of antenatal corticosteroids on childhood behavior and disabilities, including cognitive delay and cerebral palsy. STUDY DESIGN: Nonrandomized regional cohort of 541 very preterm infants born in Western Australia from singleton pregnancies and alive at 3 years were included in the study. MAIN OUTCOME MEASURES: Physical, cognitive, and psychological assessments up to 6 years. RESULTS: Increasing numbers of antenatal corticosteroid courses were associated with a reduction in the rate of cerebral palsy. Three or more courses were also associated with increased rates of aggressive/destructive, distractible, and hyperkinetic behavior and these effects were present at both ages 3 and 6 years. Measures of internalizing behavior and intelligence quotient were unaffected by antenatal corticosteroid use. CONCLUSION: Repeated antenatal courses of corticosteroids may protect against cerebral palsy but are associated with hyperactivity later in childhood.

Impact of postnatal depression on breastfeeding duration.

BACKGROUND: Postnatal depression can cause adverse effects on both mother and infant, but its impact on breastfeeding duration is poorly understood. The aim of this study was to investigate the relationship between maternal postnatal depression and breastfeeding duration. METHODS: A cohort of 1745 women was recruited on the postnatal wards of two large Australian obstetric hospitals. Self-report questionnaires were completed at recruitment, and at 2, 6, and 12 months postpartum. Breastfeeding status was determined at each follow-up, and the Edinburgh Postnatal Depression Scale was used to screen for symptoms of depression. Diagnostic psychological interviews were conducted on a subsample of women at each interval. RESULTS: Breastfeeding was initiated by 96 percent of the participants; at 2 months 79 percent were still breastfeeding, 57 percent at 6 months, and 22 percent at 12 months. Of the 18 percent of participants diagnosed with postnatal depression, the onset occurred before 2 months in 63 percent of cases. Median duration of breastfeeding was 26 weeks for women with early-onset depression, 28 weeks for women with late-onset depression, and 39 weeks for women without depression. After adjustment for confounding factors, early cessation of breastfeeding was found to be significantly associated with postnatal depression (adjusted hazard ratio 1.25, 95% CI 1.03-1.52). Onset of postnatal depression occurred before cessation of breastfeeding in most cases. CONCLUSIONS: Postnatal depression has a significant negative impact on breastfeeding duration. Assistance with breastfeeding issues should be included in the management of postnatal depression.

Stress debriefing after childbirth: a randomised controlled trial.

OBJECTIVE: To test whether critical incident stress debriefing after childbirth reduces the incidence of postnatal psychological disorders. DESIGN: Randomised single-blind controlled trial stratified for parity and delivery mode. SETTING: Two large maternity hospitals in Perth. PARTICIPANTS: 1745 women who delivered healthy term infants between April 1996 and December 1997 (875 allocated to intervention and 870 to control group). INTERVENTION: An individual, standardised debriefing session based on the principles of critical incident stress debriefing carried out within 72 hours of delivery. MAIN OUTCOME MEASURES: Diagnosis of stress disorders or depression in the 12 months postpartum, using structured psychological interview and criteria of the Diagnostic and statistical manual of mental disorders, 4th edition. RESULTS: Follow-up information was available for 1730 women (99.1%), 482 of whom underwent psychological interview. There were no significant differences between control and intervention groups in scores on Impact of Events or Edinburgh Postnatal Depression Scales at 2, 6 or 12 months postpartum, or in proportions of women who met diagnostic criteria for a stress disorder (intervention, 0.6% v control, 0.8%; P = 0.58) or major or minor depression (intervention, 17.8% v control, 18.2%; relative risk [95% CI], 0.99 [0.87-1.11]) during the postpartum year. Nor were there differences in median time to onset of depression (intervention, 6 [interquartile range, 4-9] weeks v control, 4 [3-8] weeks; P = 0.84), or duration of depression (intervention, 24 [12-46] weeks v control, 22 [10-52] weeks; P = 0.98). CONCLUSIONS: There is a high prevalence of depression in women during the first year after childbirth. A session of midwife-led, critical incident stress debriefing was not effective in preventing postnatal psychological disorders, but had no adverse effects.