A step closer to parenthood with non-obstructive azoospermia: Unveiling the impact of microdissection testicular sperm extraction in Australia's largest single-centre study.

BACKGROUND: Non-obstructive azoospermia (NOA) diagnosis poses challenges for couples seeking parenthood. Microdissection testicular sperm extraction (MD-TESE) excels in retrieving testicular sperm cells for NOA cases. However, limited live birth data in Australian NOA patients hinders accurate counselling. AIMS: This study aimed to determine the likelihood of infertile couples with a male partner diagnosed with NOA conceiving biological children using MD-TESE / intracytoplasmic sperm injection (ICSI). MATERIALS AND METHODS: A retrospective cohort study included 108 NOA men treated at a public fertility unit and a private fertility centre (May 2009-May 2022). PRIMARY OUTCOME: live birth rate (LBR); secondary outcomes: sperm retrieval rate, pregnancy rate, and neonatal outcomes. RESULTS: Among 108 patients undergoing MD-TESE, the positive sperm retrieval rate (PSRR) was 64.8% (70/108). Histology best predicted sperm retrieval success, with hypo-spermatogenesis yielding a 94.1% PSRR. Age, testicular volume, and hormonal parameters had no significant impact. Mean male age: 35.4 years; mean partner age: 32.7 years. Fertilisation rate: 50.7%. LBR per initiated cycle: 58.7% (37/63); per embryo transfer: 63.8% (37/58); per initially diagnosed NOA man: 34.3% (37/108). Cumulative LBR: 74.1% (43/58); twin rate: 10.8% (4/37). No neonatal deaths or defects were observed among 47 live offspring. CONCLUSION: This study provides valuable data for counselling NOA couples on the probability of conceiving biological offspring. MD-TESE and ICSI yielded favourable PSRR (64.8%) and LBR (63.8%). However, couples should be aware that once NOA is confirmed, the chance of taking home a baby is 34%.

Re-imaging healthcare delivery in the era of COVID-19.

The COVID-19 pandemic has exposed the deficiencies of the current healthcare system in terms of a disconnect between primary and tertiary care and increasing subspecialisation, the focus on acute episodic care rather than on prevention in a time where chronic disease prevails and an inefficient use of healthcare resources. Herein, we present the case for an alternative model of healthcare delivery - shared medical appointments - which are efficient, effective and empowering and can be transitioned to the virtual environment successfully. We highlight the barriers to implementation and how these can be overcome.

Post-warming embryo morphology is associated with live birth: a cohort study of single vitrified-warmed blastocyst transfer cycles.

PURPOSE: This study aims to examine whether blastocyst morphology post-warming correlates with live birth. METHODS: In this cohort study, morphological characteristics post-warming were reviewed in all single vitrified-warmed blastocyst transfer cycles performed between November 2016 and May 2017. Immediately before transfer, the degree of blastocoel re-expansion was graded as A, fully expanded; B, partially expanded ≥ 50%; C, partially expanded < 50%; and D, collapsed. The degree of post-warming cell survival was graded on a scale of 50 to 100% and was then classified into 4 groups: very low 50-70%, low 71-80%, moderate 81-90%, and high 91-100%. RESULTS: Overall, 612 cycles were reviewed, of which 196 included PGT-A tested embryos. The live birth rate (LBR) increased from 11.4% in the collapsed blastocysts group to 38.9% in the post-warming full re-expansion group (p < 0.001) and from 6.5% for blastocysts with a very low cell survival rate to 34.7% for blastocysts with high cell survival rate (p = 0.001). LBR was 6.7% for blastocysts with the worst post-warming morphological characteristics, namely, collapsed with very low cell survival rate. On multivariate analyses, partial blastocyst re-expansion ≥ 50%, full re-expansion, and high cell survival rate remained significantly associated with live birth, after controlling for female age, pre-vitrification morphological grading, and PGT-A. A sub-analysis of cycles using PGT-A tested embryos showed similar results. CONCLUSION: Post-warming re-expansion and high cell survival rate are associated with higher LBR in euploid and untested blastocysts. However, embryos with poor post-warming morphology still demonstrate a considerable probability of live birth, and they should not be discarded.

Thromboprophylaxis in lower limb immobilisation after injury (TiLLI).

Venous thromboembolic disease is a major global cause of morbidity and mortality. An estimated 10 million episodes are diagnosed yearly; over half of these episodes are provoked by hospital admission/procedures and result in significant loss of disability adjusted life years. Temporary lower limb immobilisation after injury is a significant contributor to the overall burden of venous thromboembolism (VTE). Existing evidence suggests that pharmacological prophylaxis could reduce overall VTE event rates in these patients, but the proportional reduction of symptomatic events remains unclear. Recent studies have used different pharmacological agents, dosing regimens and outcome measures. Consequently, there is wide variation in thromboprophylaxis strategies, and international guidelines continue to offer conflicting advice for clinicians. In this review, we provide a summary of recent evidence assessing both the clinical and cost effectiveness of thromboprophylaxis in patients with temporary immobilisation after injury. We also examine the evidence supporting stratified thromboprophylaxis and the validity of widely used risk assessment methods.

Rheumatoid arthritis treated with 6-months of first-line biologic or biosimilar therapy: an updated systematic review and network meta-analysis.

OBJECTIVES: The aim of this study was to estimate the effectiveness of first-line biologic disease modifying drugs(boDMARDs), and their approved biosimilars (bsDMARDs), compared with conventional (csDMARD) treatment, in terms of ACR (American College of Rheumatology) and EULAR (European League against Rheumatism) responses. METHODS: Systematic literature search, on eight databases to January 2017, sought ACR and EULAR data from randomized controlled trials (RCTs) of boDMARDs / bsDMARDs (in combination with csDMARDs, or monotherapy). Two adult populations: methotrexate (MTX)-naïve patients with severe active RA; and csDMARD-experienced patients with moderate-to-severe active RA. Network meta-analyses (NMA) were conducted using a Bayesian Markov chain Monte Carlo simulation using a random effects model with a probit link function for ordered categorical. RESULTS: Forty-six RCTs met the eligibility criteria. In the MTX-naïve severe active RA population, no biosimilar trials meeting the inclusion criteria were identified. MTX plus methylprednisolone (MP) was most likely to achieve the best ACR response. There was insufficient evidence that combination boDMARDs was superior to intensive (two or more) csDMARDs. In the csDMARD-experienced, moderate-to-severe RA population, the greatest effects for ACR responses were associated with tocilizumab (TCZ) monotherapy, and combination therapy (plus MTX) with bsDMARD etanercept (ETN) SB4, boDMARD ETN and TCZ. These treatments also had the greatest effects on EULAR responses. No clear differences were found between the boDMARDs and their bsDMARDs. CONCLUSIONS: In MTX-naïve patients, there was insufficient evidence that combination boDMARDs was superior to two or more csDMARDs. In csDMARD-experienced patients, boDMARDs and bsDMARDs were comparable and all combination boDMARDs / bsDMARDs were superior to single csDMARD.

MicroRNA-transcription factor interactions and their combined effect on target gene expression in colon cancer cases.

Transcription factors (TFs) and microRNAs (miRNAs) regulate gene expression: TFs by influencing messenger RNA (mRNA) transcription and miRNAs by influencing mRNA translation and transcript degradation. Additionally, miRNAs and TFs alter each other's expression, making it difficult to ascertain the effect either one has on target gene (TG) expression. In this investigation, we use a two-way interaction model with the TF and miRNA as independent variables to investigate whether miRNAs and TFs work together to influence TG expression levels in colon cancer subjects. We used known TF binding sites and validated miRNA targets to determine potential miRNA-TF-TG interactions, restricting interactions to those with a TF previously associated with altered risk of colorectal cancer death. We analyzed interactions using normal colonic mucosa expression as well as differential expression, which is measured as colonic carcinoma expression minus normal colonic mucosa expression. We analyzed 3518 miRNA-TF-TG triplets using normal mucosa expression and 617 triplets using differential expression. Normal colonic RNA-Seq data were available for 168 individuals; of these, 159 also had carcinoma RNA-Seq data. Thirteen unique miRNA-TF-TG interactions, comprising six miRNAs, four TFs, and 11 TGs, were statistically significant after adjustment for multiple comparisons in normal colonic mucosa, and 14 unique miRNA-TF-TG interactions, comprising two miRNAs, two TFs, and 13 TGs, were found for carcinoma-normal differential expression. Our results show that TG expression is influenced by both miRNAs as well as TFs, and the influence of one regulator impacts the effect of the other on the shared TG expression.

Power in pairs: assessing the statistical value of paired samples in tests for differential expression.

BACKGROUND: When genomics researchers design a high-throughput study to test for differential expression, some biological systems and research questions provide opportunities to use paired samples from subjects, and researchers can plan for a certain proportion of subjects to have paired samples. We consider the effect of this paired samples proportion on the statistical power of the study, using characteristics of both count (RNA-Seq) and continuous (microarray) expression data from a colorectal cancer study. RESULTS: We demonstrate that a higher proportion of subjects with paired samples yields higher statistical power, for various total numbers of samples, and for various strengths of subject-level confounding factors. In the design scenarios considered, the statistical power in a fully-paired design is substantially (and in many cases several times) greater than in an unpaired design. CONCLUSIONS: For the many biological systems and research questions where paired samples are feasible and relevant, substantial statistical power gains can be achieved at the study design stage when genomics researchers plan on using paired samples from the largest possible proportion of subjects. Any cost savings in a study design with unpaired samples are likely accompanied by underpowered and possibly biased results.

The PI3K/AKT signaling pathway: Associations of miRNAs with dysregulated gene expression in colorectal cancer.

The PI3K/AKT-signaling pathway is one of the most frequently activated signal-transduction pathways in cancer. We examined how dysregulated gene expression is associated with miRNA expression in this pathway in colorectal cancer (CRC). We used data from 217 CRC cases to evaluate differential pathway gene expression between paired carcinoma and normal mucosa and identify miRNAs that are associated with these genes. Gene expression data from RNA-Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were analyzed. We focused on genes most associated with CRC (fold change (FC) of >1.5 or <0.67) that were statistically significant after adjustment for multiple comparisons. Of the 304 genes evaluated, 76 had a FC of <0.67, and 57 had a FC of >1.50; 47 of these genes were associated with miRNA differential expression. There were 145 mRNA:miRNA seed-region matches of which 26 were inversely associated suggesting a greater likelihood of a direct association. Most miRNA:mRNA associations were with factors that stimulated the pathway. For instance, both IL6R and PDGFRA had inverse seed-region matches with seven miRNAs, suggesting that these miRNAs have a direct effect on these genes and may be key elements in activation of the pathway. Other miRNA:mRNA associations with similar impact on the pathway were miR-203a with ITGA4, miR-6071 with ITGAV, and miR-375 with THBS2, all genes involved in extracellular matrix function that activate PI3Ks. Gene expression in the PI3K/Akt-signaling pathway is dysregulated in CRC. MiRNAs were associated with many of these dysregulated genes either directly or in an indirect manner.

Infrequently expressed miRNAs in colorectal cancer tissue and tumor molecular phenotype.

This corrects the article DOI: 10.1038/modpathol.2017.38.

Estimating Future Health Technology Diffusion Using Expert Beliefs Calibrated to an Established Diffusion Model.

OBJECTIVES: Estimates of future health technology diffusion, or future uptake over time, are a requirement for different analyses performed within health technology assessments. Methods for obtaining such estimates include constant uptake estimates based on expert opinion or analogous technologies and on extrapolation from initial data points using parametric curves-but remain divorced from established diffusion theory and modeling. We propose an approach to obtaining diffusion estimates using experts' beliefs calibrated to an established diffusion model to address this methodologic gap. METHODS: We performed an elicitation of experts' beliefs on future diffusion of a new preterm birth screening illustrative case study technology. The elicited quantities were chosen such that they could be calibrated to yield the parameters of the Bass model of new product growth, which was chosen based on a review of the diffusion literature. RESULTS: With the elicitation of only three quantities per diffusion curve, our approach enabled us to quantify uncertainty about diffusion of the new technology in different scenarios. Pooled results showed that the attainable number of adoptions was predicted to be relatively low compared with what was thought possible. Further research evidence improved the attainable number of adoptions only slightly but resulted in greater speed of diffusion. CONCLUSIONS: The proposed approach of eliciting experts' beliefs about diffusion and informing the Bass model has the potential to fill the methodologic gap evident in value of implementation and research, as well as budget impact and some cost-effectiveness analyses.

Absorption and Safety With Sustained Use of RELiZORB Evaluation (ASSURE) Study in Patients With Cystic Fibrosis Receiving Enteral Feeding.

OBJECTIVES: Pancreatic insufficiency (PI) and malabsorption of fats lead to reduced caloric intake, inability to maintain weight, and increased gastrointestinal symptoms. Thus, enteral nutrition (EN) is used in patients with cystic fibrosis (CF) and poor nutritional status. The current study evaluated safety, tolerability, and improvement of fatty acid (FA) status in red blood cell (RBC) membranes, a marker of long-term FA absorption, with an in-line digestive cartridge (RELiZORB) that hydrolyzes fat in enteral formula. METHODS: Patients with CF receiving EN participated in a multicenter, 90-day open-label study during which RELiZORB was used with overnight EN. The primary endpoint was change over time in RBC uptake of docosahexaenoic acid (DHA)+ eicosapentaenoic acid (EPA). Gastrointestinal symptoms were collected to evaluate safety and tolerability. Several clinical and anthropometric parameters were also assessed throughout the study. RESULTS: A total of 36 subjects completed the study with a mean age of 13.8 years, body mass index of 17.7 and 6.2 years mean use of overnight EN. Fat absorption significantly improved as shown by increased RBC levels of DHA+EPA, improved ω-6/ω-3 ratio, and increased plasma levels of DHA+EPA. RELiZORB use was not associated with any unanticipated adverse events. CONCLUSIONS: RELiZORB use was found to be safe, well tolerated, and resulted in increased levels of FAs in RBCs and plasma. This is the first prospective study to show EN can improve FA abnormalities in CF. Because improvement in omega-3 levels has been shown to help pulmonary and inflammatory status as well as anthropometric parameters in CF, RELiZORB may have important long-term therapeutic benefits in patients with CF.

The miRNA landscape of colorectal polyps.

The genomic landscape of adenomas and polyps may help define disease pathways. Expression of miRNAs in adenomas and polyps may importantly contribute to these pathways. We evaluated miRNA expression in 293 polyp-normal colorectal mucosa pairs. Polyps were classified as either adenomatous polyp (AD), hyperplastic polyp (HP), or sessile serrated polyp (SSP). We compared these miRNA expression profiles in polyps to miRNA expression in microsatellite unstable (MSI) and stable (MSS) tumors. A False Discovery Rate of 0.05 based on Benjamini and Hochberg was used to adjust for multiple comparisons. There were 70 miRNAs with differential expression by polyp type with a fold change <0.75 or >1.34 after adjusting for multiple comparisons. The major differences in miRNA expression were observed between AD and SSP and AD and HP, with few differences in expression noted for SSP and HP. AD polyps were more likely to be upregulated from normal colonic mucosa, while SSP and HP were more likely to be downregulated from normal colonic mucosa. MiRNA expression in the SSP and HP tumors almost uniformly go in opposite directions from the MSS tumor miRNA expression and was mixed with MSI tumors. We conclude that different types of polyps have unique miRNA expression profiles. © 2017 Wiley Periodicals, Inc.

Transcription factor-microRNA associations and their impact on colorectal cancer survival.

MicroRNAs (miRNAs) and Transcription Factors (TFs) both influence messenger RNA (mRNA) expression, disrupting biological pathways involved in carcinogenesis and prognosis. As many miRNAs target multiple mRNAs, thus influencing a multitude of biological pathways, deciphering which miRNAs are important for cancer development and survival is difficult. In this study, we (i) determine associations between TF and survival (N = 168 colon cancer cases); (ii) identify miRNAs associated with TFs related to survival; and (iii) determine if factors derived from TF-specific miRNA principal component analysis (PCA) influence survival. Cox Proportional hazard models were run for each PCA factor to determine Hazard Ratios (HR) and 95% Confidence Intervals (CI) adjusting for age, center, and AJCC stage. Thirty TFs improved survival when differential expression increased; 27 of these were associated significantly with normal colonic mucosa expression of 65 unique miRNAs when an FDR q-value of <0.05 was applied. Five factors, comprising 21 miRNAs, altered survival in rectal cancer subjects; four of these five factors improved survival and one factor reduced survival. One factor comprising four miRNAs reduced survival in colon cancer subjects. In summary, our data suggest that expression of TFs and their related miRNAs influence survival after diagnosis with colorectal cancer.

Alterations in microRNA expression associated with alcohol consumption in rectal cancer subjects.

PURPOSE: Alcohol consumption has been purported to influence many diseases. MicroRNAs (miRNAs) may be influenced by compounds found in alcohol. In this investigation, we test the hypothesis that total alcohol, beer, wine, and hard liquor influence miRNA expression. METHODS: We studied 1447 colorectal (CR) cancer cases with normal CR mucosa and carcinoma miRNA expression data along with alcohol consumption data. We analyzed long-term and long-term and current (LTC) alcohol use for beer, liquor, and wine with miRNA expression between paired carcinoma and normal colon and rectal tissues, adjusting for multiple comparisons using the positive false discovery rate q-value. MiRNAs associated significantly with alcohol were examined with all-cause mortality (ACM). MiRNAs associated significantly with ACM were examined with RNA-Seq data. RESULTS: Expression of 84 miRNAs was associated significantly with LTC wine use in normal rectal mucosa. Higher expression of two of these miRNAs significantly worsened ACM: hsa-miR-210 (Hazard Ratio [HR] 1.12, 95% CI (1.03, 1.21), p-value = 0.004), and hsa-miR-92a-1-5p (HR 1.20, 95% CI (1.04, 1.38), p-value = 0.013). These miRNAs were downregulated across levels of LTC wine consumption. CONCLUSIONS: Our results suggest that wine influences miRNA expression in rectal cancer, supporting the hypothesis that components in alcohol influence miRNA expression.

Infrequently expressed miRNAs in colorectal cancer tissue and tumor molecular phenotype.

We have previously shown that commonly expressed miRNAs influenced tumor molecular phenotype in colorectal cancer. We hypothesize that infrequently expressed miRNAs, when showing higher levels of expression, help to define tumor molecular phenotype. In this study, we examine 304 miRNAs expressed in at least 30 individuals, but in <50% of the population and with a mean level of expression above 1.0 relative florescent unit. We examine associations in 1893 individuals who have the tumor molecular phenotype data as well as miRNA expression levels for both carcinoma and normal colorectal tissue. We compare miRNAs uniquely associated with tumor molecular phenotype to the RNAseq data to identify genes associated with these miRNAs. This information is used to further identify unique pathways associated with tumor molecular phenotypes of TP53-mutated, KRAS-mutated, CpG island methylator phenotype and microsatellite instability tumors. Thirty-seven miRNAs were uniquely associated with TP53-mutated tumors; 30 of these miRNAs had higher level of expression in TP53-mutated tumors, while seven had lower levels of expression. Of the 34 miRNAs associated with CpG island methylator phenotype-high tumors, 16 were more likely to have a CpG island methylator phenotype-high tumor and 19 were less likely to be CpG island methylator phenotype-high. For microsatellite instability, 13 of the 22 infrequently expressed miRNAs were significantly less likely to be expressed in microsatellite unstable tumors. KRAS-mutated tumors were not associated with any miRNAs after adjustment for multiple comparisons. Of the dysregulated miRNAs, 17 were more likely to be TP53-mutated tumors while simultaneously being less likely to be CpG island methylator phenotype-high and/or microsatellite instability tumors. Genes regulated by these miRNAs were involved in numerous functions and pathways that influence cancer risk and progression. In summary, some infrequently expressed miRNAs, when expressed at higher levels, appear to have significant biological meaning in terms of tumor molecular phenotype and gene expression profiles.

Identifying factors associated with the direction and significance of microRNA tumor-normal expression differences in colorectal cancer.

BACKGROUND: microRNAs are small non-protein-coding RNA molecules that regulate gene expression, and have a potential epigenetic role in disease progression and survival of colorectal cancer. In terms of tumor-normal expression differences, many microRNAs exhibit evidence of being up-regulated in some subjects but down-regulated in others, or are dysregulated only for a subset of the population. We present and implement an approach to identify factors (lifestyle, tumor molecular phenotype, and survival-related) that are associated with the direction and/or significance of these microRNAs' tumor-normal expression differences in colorectal cancer. METHODS: Using expression data for 1394 microRNAs and 1836 colorectal cancer subjects (each with both tumor and normal samples), we perform a dip test to identify microRNAs with multimodal distributions of tumor-normal expression differences. For proximal, distal, and rectal tumor sites separately, these microRNAs are tested for tumor-normal differential expression using a signed rank test, both overall and within levels of each lifestyle, tumor molecular phenotype, and survival-related factor. Appropriate adjustments are made to control the overall FDR. RESULTS: We identify hundreds of microRNAs whose direction and/or significance of tumor-normal differential expression is associated with one or more lifestyle, tumor molecular phenotype, or survival-related factors. CONCLUSIONS: The results of this study demonstrate the benefit to colorectal cancer researchers to consider multiple subject-level factors when studying dysregulation of microRNAs, whose tumor-related changes in expression can be associated with multiple factors. Our results will serve as a publicly-available resource to provide clarifying information about various factors associated with the direction and significance of tumor-normal differential expression of microRNAs in colorectal cancer.

Increased Fat Absorption From Enteral Formula Through an In-line Digestive Cartridge in Patients With Cystic Fibrosis.

OBJECTIVES: Supplemental enteral nutrition (EN) is used by approximately 12% of people with cystic fibrosis (CF). The objective of this study was to evaluate the safety, tolerability, and fat absorption of a new in-line digestive cartridge (Relizorb) that hydrolyzes fat in enteral formula provided to patients with CF. METHODS: Patients with CF receiving EN participated in a multicenter, randomized, double-blind, crossover trial with an open-label safety evaluation period. Plasma omega-3 fatty acid (FA) concentrations were measured and used as markers of fat absorption. Gastrointestinal symptoms were recorded to evaluate safety and tolerability. Information regarding the effect of EN on appetite and breakfast consumption was also collected. RESULTS: Before study entry, participants had received EN for a mean of 6.6 years at a mean volume of approximately 800 mL, yet had a mean body mass index of only 17.5 kg/m and omega-3 FA plasma concentrations were only 60% of levels found in normal healthy subjects. Compared with placebo, cartridge use resulted in a statistically significant 2.8-fold increase in plasma omega-3 FA concentrations. There were no adverse experiences associated with cartridge use, and a decrease in the frequency and severity of most symptoms of malabsorption was observed with cartridge use. Participants reported increased preservation of appetite and breakfast consumption with cartridge use compared with their pre-study regimen. CONCLUSIONS: Use of this in-line digestive cartridge was safe and well tolerated, and resulted in significantly increased levels of plasma omega-3 FA used with enteral formula, suggesting an overall increased fat absorption.

Multifaceted quality improvement initiative to decrease pediatric asthma readmissions.

BACKGROUND: Asthma is the most common chronic disease of childhood and a leading cause of hospitalization in children. A primary goal of asthma control is prevention of hospitalizations. A hospital admission is the single strongest predictor of future hospital admissions for asthma. The 30-day asthma readmission rate at our institution was significantly higher than that of other hospitals in the Children's Hospital Association. As a result, a multifaceted quality improvement project was undertaken with the goal of reducing the 30-day inpatient asthma readmission rate by 50% within two years. METHODS: Analysis of our institution's readmission patterns, value stream mapping of asthma admission, discharge, and follow-up processes, literature review, and examination of comparable successful programs around the United States were all utilized to identify potential targets for intervention. Interventions were implemented in a stepwise manner, and included increasing inhaler availability after discharge, modifying asthma education strategies, and providing in-home post-discharge follow-up. The primary outcome was a running 12-month average 30-day inpatient readmission rate. Secondary outcomes included process measures for individual interventions. RESULTS: From a peak of 7.98% in January 2013, a steady decline to 1.65% was observed by July 2014, which represented a 79.3% reduction in 30-day readmissions. CONCLUSION: A significant decrease in hospital readmissions for pediatric asthma is possible, through comprehensive, multidisciplinary quality improvement that spans the continuum of care.

Addressing engagement, anger and aggression through the Rock Water Program: Rural adolescent males' perceptions.

OBJECTIVE: The Rock and Water Program (RWP) has been implemented in some Australian schools as a means of addressing school disengagement, anger and aggression, which are significant determinants of mental illness. However, much of the evidence supporting the RWP is anecdotal. This project explored rural adolescent males' perceptions of the RWP. DESIGN: Questionnaires were used to gather data about the students prior to their commencement in the RWP. Focus group interviews were conducted with students at weeks 5 and 9 of the 9-week program. Data were analysed using thematic analysis. SETTING AND PARTICIPANTS: The RWP was facilitated in four schools in rural NSW over three terms for a total of 12 program deliveries. One hundred and eighty-seven rural adolescent males participated in the focus groups. The participants were identified by their school as disengaged in schoolwork and either perpetrators and/or victims of anger and aggression. MAIN OUTCOME: Participants liked the 'learning by doing' action-oriented approach, and reported learning strategies that could reduce aggression in the school and wider community. RESULTS: The focus groups provided insight into why these adolescent boys engaged with this program when generally engagement in school, overall, was reported as poor. Suggestions for program improvement included more or longer sessions, and the inclusion of girls. CONCLUSION: This study found that the RWP engaged rurally based boys, who spoke positively about the action-oriented program. Future research could examine if this translates into reduced incidents of anger and violence at school and improved school engagement and overall physical and mental health.

MicroRNA profiles in colorectal carcinomas, adenomas and normal colonic mucosa: variations in miRNA expression and disease progression.

MiRNAs are small, non-protein-coding RNA molecules that regulate gene expression either by post-transcriptionally suppressing mRNA translation or by mRNA degradation. We examine differentially expressed miRNAs in colorectal carcinomas, adenomas and normal colonic mucosa. Data come from population-based studies of colorectal cancer conducted in Utah and the Kaiser Permanente Medical Care Program. A total of 1893 carcinoma/normal-paired samples and 290 adenoma tissue samples were run on the Agilent Human miRNA Microarray V19.0 which contained 2006 miRNAs. We tested for significant differences in miRNA expression between paired carcinoma/adenoma/normal colonic tissue samples. Fewer than 600 miRNAs were expressed in >80% of people for colonic tissue; of these 86.5% were statistically differentially expressed between carcinoma and normal colonic mucosa using a false discovery rate of 0.05. Roughly half of these differentially expressed miRNAs showed a progression in levels of expression from normal to adenoma to carcinoma tissue. Other miRNAs appeared to be altered at the normal to adenoma stage, while others were only altered at the adenoma to carcinoma stage or only at the normal to carcinoma stage. Evaluation of the Agilent platform showed a high degree of repeatability (r = 0.98) and reasonable agreement with the NanoString platform. Our data suggest that miRNAs are highly dysregulated in colorectal tissue among individuals with colorectal cancer; the pattern of disruption varies by miRNA as tissue progresses from normal to adenoma to carcinoma.