First-Pass Meconium Samples from Healthy Term Vaginally-Delivered Neonates : An Analysis of the Microbiota

Acknowledgments The authors would like to thank the parents who consented to provide samples with limited notice at an emotional and stressful time. This work was supported entirely from personal donations to the neonatal endowments fund at Aberdeen Maternity Hospital and we thank families for their continued generosity, year-on-year. The Rowett Institute of Nutrition and Health receives funding from the Scottish Government (SG-RESAS). Funding: This work was funded from NHS Grampian Neonatal Endowments. The Rowett Institute receives funding from the Rural and Environmental Science and Analytical Services programme of the Scottish Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

An exploration of the pedagogies employed to integrate knowledge in work-integrated learning

This article describes a three‐sector, national research project that investigated the integration aspect of work‐integrated learning (WIL). The context for this study is three sectors of New Zealand higher education: business and management, sport, and science and engineering, and a cohort of higher educational institutions that offer WIL/cooperative education in variety of ways. The aims of this study were to investigate the pedagogical approaches in WIL programs that are currently used by WIL practitioners in terms of learning, and the integration of academic‐workplace learning. The research constituted a series of collective case studies, and there were two main data sources — interviews with three stakeholder groups (namely employers, students, and co‐op practitioners), and analyses of relevant documentation (e.g., course/paper outlines, assignments on reflective practice, portfolio of learning, etc.). The research findings suggest that there is no consistent mechanism by which placement coordinators, off‐campus supervisors, or mentors seek to employ or develop pedagogies to foster learning and the integration of knowledge. Learning, it seems, occurs by means of legitimate peripheral participation with off‐campus learning occurring as a result of students working alongside professionals in their area via an apprenticeship model of learning. There is no evidence of explicit attempts to integrate on‐ and off‐campus learning, although all parties felt this would and should occur. However, integration is implicitly or indirectly fostered by a variety of means such as the use of reflective journals

Планування ЗЕД на підприємствах малого та середнього бізнесу

Pheochromocytomas (PCC) and abdominal paragangliomas (PGL) display a highly diverse genetic background and recent gene expression profiling studies have shown that PCC and PGL (together PPGL) alter either kinase signaling pathways or the pseudo-hypoxia response pathway dependent of the genetic composition. Recurrent mutations in the Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been verified in sporadic PPGLs. In order to further establish the HRAS mutation frequency and to characterize the associated expression profiles of HRAS mutated tumors, 156 PPGLs for exon 2 and 3 hotspot mutations in the HRAS gene was screened, and compared with microarray-based gene expression profiles for 93 of the cases. The activating HRAS mutations G13R, Q61R, and Q61K were found in 10/142 PCC (7.0%) and a Q61L mutation was revealed in 1/14 PGL (7.1%). All HRAS mutated cases included in the mRNA expression profiling grouped in Cluster 2, and 21 transcripts were identified as altered when comparing the mutated tumors with 91 HRAS wild-type PPGL. Somatic HRAS mutations were not revealed in cases with known PPGL susceptibility gene mutations and all HRAS mutated cases were benign. The HRAS mutation prevalence of all PPGL published up to date is 5.2% (49/950), and 8.8% (48/548) among cases without a known PPGL susceptibility gene mutation. The findings support a role of HRAS mutations as a somatic driver event in benign PPGL without other known susceptibility gene mutations. HRAS mutated PPGL cluster together with NF1- and RET-mutated tumors associated with activation of kinase-signaling pathways.Funding Agencies|Swedish Cancer Foundation; StratCan; Swedish Research Council; Cancer Research Foundations of Radiumhemmet; Karolinska Institutet; Stockholm County Council</p

MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension

Rationale: The pathogenesis of PAH remains unclear. The four microRNAs representing the miR-143 and miR-145 stem loops are genomically clustered. Objective: To elucidate the transcriptional regulation of the miR-143/145 cluster, and the role of miR-143 in PAH. Methods and Results: We identified the promoter region that regulates miR-143/145 miRNA expression in pulmonary artery smooth muscle cells (PASMCs). We mapped PAH-related signalling pathways, including estrogens receptor (ER), liver X factor/retinoic X receptor (LXR/RXR), TGF-β (Smads), and hypoxia (HRE) that regulated levels of all pri-miR stem loop transcription and resulting miRNA expression. We observed that miR-143-3p is selectively upregulated compared to miR-143-5p during PASMC migration. Modulation of miR-143 in PASMCs significantly altered cell migration and apoptosis. In addition, we found high abundance of miR-143-3p in PASMCs-derived exosomes. Using assays with pulmonary arterial endothelial cells (PAECs) we demonstrated a paracrine pro-migratory and pro-angiogenic effect of miR-143-3p enriched exosomes from PASMC. Quantitative PCR and in situ hybridisation showed elevated expression of miR-143 in calf models of PAH as well as in samples from PAH patients. Moreover, in contrast to our previous findings that had not supported a therapeutic role in vivo, we now demonstrate a protective role for miR-143 in experimental PH in vivo in miR-143-/- and antimiR143-3p-treated mice exposed to chronic hypoxia in both preventative and reversal settings. Conclusions: MiR-143-3p modulated both cellular and exosome-mediated responses in pulmonary vascular cells, while inhibition of miR-143-3p blocked experimental PH. Taken together these findings confirm an important role for the miR-143/145 cluster in PAH pathobiology

Investigating the prostate specific antigen, body mass index and age relationship:is an age–BMI-adjusted PSA model clinically useful?

Purpose Previous studies indicate a possible inverse relationship between prostate-specific antigen (PSA) and body mass index (BMI), and a positive relationship between PSA and age. We investigated the associations between age, BMI, PSA, and screen-detected prostate cancer to determine whether an age–BMI-adjusted PSA model would be clinically useful for detecting prostate cancer. Methods Cross-sectional analysis nested within the UK ProtecT trial of treatments for localized cancer. Of 18,238 men aged 50–69 years, 9,457 men without screen-detected prostate cancer (controls) and 1,836 men with prostate cancer (cases) met inclusion criteria: no history of prostate cancer or diabetes; PSA\10 ng/ml; BMI between 15 and 50 kg/m2. Multivariable linear regression models were used to investigate the relationship between log-PSA, age, and BMI in all men, controlling for prostate cancer status. Results In the 11,293 included men, the median PSA was 1.2 ng/ml (IQR: 0.7–2.6); mean age 61.7 years (SD 4.9); and mean BMI 26.8 kg/m2 (SD 3.7). There were a 5.1% decrease in PSA per 5 kg/m2 increase in BMI (95% CI 3.4–6.8) and a 13.6% increase in PSA per 5-year increase in age (95% CI 12.0–15.1). Interaction tests showed no evidence for different associations between age, BMI, and PSA in men above and below 3.0 ng/ml (all p for interaction [0.2). The age–BMI-adjusted PSA model performed as well as an age-adjusted model based on National Institute for Health and Care Excellence (NICE) guidelines at detecting prostate cancer. Conclusions Age and BMI were associated with small changes in PSA. An age–BMI-adjusted PSA model is no more clinically useful for detecting prostate cancer than current NICE guidelines. Future studies looking at the effect of different variables on PSA, independent of their effect on prostate cancer, may improve the discrimination of PSA for prostate cancer.</p

Sindbis virus polyarthritis outbreak signalled by virus prevalence in the mosquito vectors

Polyarthritis and rash caused by Sindbis virus (SINV), was first recognised in northern Europe about 50 years ago and is known as Ockelbo disease in Sweden and Pogosta disease in Finland. This mosquito-borne virus occurs mainly in tropical and sub-tropical countries, and in northern Europe it is suggested to cause regularly reoccurring outbreaks. Here a seven-year cycle of SINV outbreaks has been referred to in scientific papers, although the hypothesis is based solely on reported human cases. In the search for a more objective outbreak signal, we evaluated mosquito abundance and SINV prevalence in vector mosquitoes from an endemic area in central Sweden. Vector mosquitoes collected in the River Dalälven floodplains during the years before, during, and after the hypothesised 2002 outbreak year were assayed for virus on cell culture. Obtained isolates were partially sequenced, and the nucleotide sequences analysed using Bayesian maximum clade credibility and median joining network analysis. Only one SINV strain was recovered in 2001, and 4 strains in 2003, while 15 strains were recovered in 2002 with significantly increased infection rates in both the enzootic and the bridge-vectors. In 2002, the Maximum Likelihood Estimated infection rates were 10.0/1000 in the enzootic vectors Culex torrentium/pipiens, and 0.62/1000 in the bridge-vector Aedes cinereus, compared to 4.9/1000 and 0.0/1000 in 2001 and 0.0/1000 and 0.32/1000 in 2003 Sequence analysis showed that all isolates belonged to the SINV genotype I (SINV-I). The genetic analysis revealed local maintenance of four SINV-I clades in the River Dalälven floodplains over the years. Our findings suggest that increased SINV-I prevalence in vector mosquitoes constitutes the most valuable outbreak marker for further scrutinising the hypothesized seven-year cycle of SINV-I outbreaks and the mechanisms behind

Validating the use of hospital episode statistics data and comparison of costing methodologies for economic evaluation:An end-of-life case study from the cluster randomised triAl of PSA testing for prostate cancer (CAP)

Objectives To evaluate the accuracy of routine data for costing inpatient resource use in a large clinical trial and to investigate costing methodologies. Design Final-year inpatient cost profiles were derived using (1) data extracted from medical records mapped to the National Health Service (NHS) reference costs via service codes and (2) Hospital Episode Statistics (HES) data using NHS reference costs. Trust finance departments were consulted to obtain costs for comparison purposes. Setting 7 UK secondary care centres. Population A subsample of 292 men identified as having died at least a year after being diagnosed with prostate cancer in Cluster randomised triAl of PSA testing for Prostate cancer (CAP), a long-running trial to evaluate the effectiveness and cost-effectiveness of prostate-specific antigen (PSA) testing. Results Both inpatient cost profiles showed a rise in costs in the months leading up to death, and were broadly similar. The difference in mean inpatient costs was £899, with HES data yielding ∼8% lower costs than medical record data (differences compatible with chance, p=0.3). Events were missing from both data sets. 11 men (3.8%) had events identified in HES that were all missing from medical record review, while 7 men (2.4%) had events identified in medical record review that were all missing from HES. The response from finance departments to requests for cost data was poor: only 3 of 7 departments returned adequate data sets within 6 months. Conclusions Using HES routine data coupled with NHS reference costs resulted in mean annual inpatient costs that were very similar to those derived via medical record review; therefore, routinely available data can be used as the primary method of costing resource use in large clinical trials. Neither HES nor medical record review represent gold standards of data collection. Requesting cost data from finance departments is impractical for large clinical trials.</p