Spatio-temporal quantile regression analysis revealing more nuanced patterns of climate change: A study of long-term daily temperature in Australia.

Many studies have considered temperature trends at the global scale, but the literature is commonly associated with an overall increase in mean temperature in a defined past time period and hence lacking in in-depth analysis of the latent trends. For example, in addition to heterogeneity in mean and median values, daily temperature data often exhibit quasi-periodic heterogeneity in variance, which has largely been overlooked in climate research. To this end, we propose a joint model of quantile regression and variability. By accounting appropriately for the heterogeneity in these types of data, our analysis using Australian data reveals that daily maximum temperature is warming by ∼0.21°C per decade and daily minimum temperature by ∼0.13°C per decade. More interestingly, our modeling also shows nuanced patterns of change over space and time depending on location, season, and the percentiles of the temperature series.

Field studies of pollutant removal from nursery and greenhouse runoff by constructed wetlands.

Plant nursery runoff commonly contains pesticides and nutrients that often threaten aquatic ecosystems. Constructed wetlands could be a tool to remove pesticides and nutrients from nursery runoff but have not been extensively studied in this setting. Two field-scale constructed wetlands (one subsurface-flow constructed wetland [SFCW] and one free-surface constructed wetland [FSCW]) were implemented and monitored for water quality improvement. The SFCW demonstrated significant mass reduction of 78% or greater for nitrate, orthophosphate, total nitrogen, total phosphorus, and total suspended solids. The SFCW also demonstrated significant mass reduction of 79% or greater for 10 of the 12 pesticide compounds detected in over half of the collected samples. The FSCW demonstrated significant mass reduction of 46% or greater for all nonpesticide analytes except total nitrogen. Loading rate and actual storage volume compared with inflow volume likely affected performance. Reduced size and increased loading rate of the FSCW likely reduced its ability to effectively reduce pesticides. Results from this study indicate that constructed wetlands are likely an effective tool for nursery runoff management. When designing and implementing constructed wetlands, it is important for practitioners to consider the tradeoff between system size (additional cost and land otherwise dedicated to production) and performance.

Correction to: Twenty-five years on: revisiting Bosnia and Herzegovina after implementation of a family medicine development program.

Following publication of the original article [1], the authors opted to correct the name of co-author Amra Zalihic from Zahilic to Zalihic. The original article has been corrected.

Twenty-five years on: revisiting Bosnia and Herzegovina after implementation of a family medicine development program.

BACKGROUND: The wars that ravaged the former Socialist Federal Republic of Yugoslavia in the 1990's resulted in the near destruction of the healthcare system, including education of medical students and the training of specialist physicians. In the latter stages of the war, inspired by Family Medicine programs in countries such as Canada, plans to rebuild a new system founded on a strong primary care model emerged. Over the next fifteen years, the Queen's University Family Medicine Development Program in Bosnia and Herzegovina played an instrumental role in rebuilding the primary care system through educational initiatives at the undergraduate, residency, Masters, PhD, and continuing professional development levels. Changes were supported by new laws and regulations to insure sustainability. This study revisited Bosnia and Herzegovina (B-H) 8-years after the end of the program to explore the impact of initiatives through understanding the perspectives and experiences of individuals at all levels of the primary care system from students, deans of medical schools, Family Medicine residents, practicing physicians, Health Center Directors and Association Leaders. METHODS: Qualitative exploratory design using purposeful sampling. Semi-structured interviews and focus groups with key informants were conducted in English or with an interpreter as needed and audiotaped. Transcripts and field notes were analyzed using an interpretative phenomenological approach to identify major themes and subthemes. RESULTS: Overall, 118 participants were interviewed. Three major themes and 9 subthemes were identified including (1) The Development of Family Medicine Education, (subthemes: establishment of departments of family medicine, undergraduate medical curriculum change), (2) Family Medicine as a Discipline (Family Medicine specialization, academic development, and Family Medicine Associations), and (3) Health Care System Issues (continuity of care, comprehensiveness of care, practice organization and health human resources). CONCLUSIONS: Despite the impact of years of war and the challenges of a complex and unstable postwar environment, initiatives introduced by the Queen's Program succeeded in establishing sustainable changes, allowing Family Medicine in B-H to continue to adapt without abandoning its strong foundations. Despite the success of the program, the undervaluing of Primary Care from a human resource and health finance perspective presents ongoing threats to the system.

Bridging the gap in genetics: a progressive model for primary to specialist care.

BACKGROUND: The rapid expansion of genetic knowledge, and the implications for healthcare has resulted in an increased role for Primary Care Providers (PCPs) to incorporate genetics into their daily practice. The objective of this study was to explore the self-identified needs, including educational needs, of both urban and rural Primary Care Providers (PCPs) in order to provide genetic care to their patients. METHODS: Using a qualitative grounded theory approach, ten key informant interviews, and one urban and two rural PCP focus groups (FGs) (n = 19) were conducted. All PCPs practiced in Southeastern Ontario. Data was analyzed using a constant comparative method and thematic design. The data reported here represent a subset of a larger study. RESULTS: Participants reported that PCPs have a responsibility to ensure patients receive genetic care. However, specific roles and responsibilities for that care were poorly defined. PCPs identified a need for further education and resources to enable them to provide care for individuals with genetic conditions. Based on the findings, a progressive stepped model that bridges primary and specialty genetic care was developed; the model ranged from PCPs identifying patients with genetic conditions that they could manage alone, to patients who they could manage with informal or electronic consultation to those who clearly required specialist referral. CONCLUSIONS: PCPs identified a need to integrate genetics into primary care practice but they perceived barriers including a lack of knowledge and confidence, access to timely formal and informal consultation and clearly defined roles for themselves and specialists. To address gaps in PCP confidence in providing genetic care, interventions that are directed at accessible just-in-time support and consultation have the potential to empower PCPs to manage patients' genetic conditions. Specific attention to content, timing, and accessibility of educational interventions is critical to address the needs of both urban and rural PCPs. A progressive framework for bridging primary to specialty care through a 'stepped' model for providing continuing medical education, and genetic care can was developed and can be used to guide future design and delivery of educational interventions and resources.

Primary care providers' lived experiences of genetics in practice.

To effectively translate genetic advances into practice, engagement of primary care providers (PCPs) is essential. Using a qualitative, phenomenological methodology, we analyzed key informant interviews and focus groups designed to explore perspectives of urban and rural PCPs. PCPs endorsed a responsibility to integrate genetics into their practices and expected advances in genetic medicine to expand. However, PCPs reported limited knowledge and difficulties accessing resources, experts, and continuing education. Rural practitioners' additional concerns included cost, distance, and poor patient engagement. PCPs' perspectives are crucial to develop relevant educational and systems-based interventions to further expand genetic medicine in primary care.

Helper-Dependent Chain Reaction (HDCR) for Selective Amplification of Methylated DNA Sequences.

Over the last few years a number of restriction enzymes that cut DNA only if cytosines within their recognition sequences are methylated have been characterized and become commercially available. Cleavage with these enzymes to release DNA fragments in a methylation-dependent manner can be combined with a novel method of amplification, Helper Dependent Chain Reaction (HDCR), to selectively amplify these fragments. HDCR uses "Helper" oligonucleotides as templates for extension of the free 3' end of target fragments to incorporate tag sequences at the ends of fragments. These tag sequences are then used for priming of amplification of target fragments. Modifications to the amplification primers (Drivers) and the Helpers ensure that there is selection for the sequences within target fragments with each cycle of amplification. The combination of methylation-dependent enzymes and HDCR allows the sensitive and selective amplification of methylated DNA sequences without the need for bisulfite treatment.

Evaluation of Methylation Biomarkers for Detection of Circulating Tumor DNA and Application to Colorectal Cancer.

Solid tumors shed DNA into circulation, and there is growing evidence that the detection of circulating tumor DNA (ctDNA) has broad clinical utility, including monitoring of disease, prognosis, response to chemotherapy and tracking tumor heterogeneity. The appearance of ctDNA in the circulating cell-free DNA (ccfDNA) isolated from plasma or serum is commonly detected by identifying tumor-specific features such as insertions, deletions, mutations and/or aberrant methylation. Methylation is a normal cell regulatory event, and since the majority of ccfDNA is derived from white blood cells (WBC), it is important that tumour-specific DNA methylation markers show rare to no methylation events in WBC DNA. We have used a novel approach for assessment of low levels of DNA methylation in WBC DNA. DNA methylation in 29 previously identified regions (residing in 17 genes) was analyzed in WBC DNA and eight differentially-methylated regions (DMRs) were taken through to testing in clinical samples using methylation specific PCR assays. DMRs residing in four genes, BCAT1, GRASP, IKZF1 and IRF4, exhibited low positivity, 3.5% to 7%, in the plasma of colonoscopy-confirmed healthy subjects, with the sensitivity for detection of ctDNA in colonoscopy-confirmed patients with colorectal cancer being 65%, 54.5%, 67.6% and 59% respectively.

Evaluation of a universal flow-through model for predicting and designing phosphorus removal structures.

Phosphorus (P) removal structures have been shown to decrease dissolved P loss from agricultural and urban areas which may reduce the threat of eutrophication. In order to design or quantify performance of these structures, the relationship between discrete and cumulative removal with cumulative P loading must be determined, either by individual flow-through experiments or model prediction. A model was previously developed for predicting P removal with P sorption materials (PSMs) under flow-through conditions, as a function of inflow P concentration, retention time (RT), and PSM characteristics. The objective of this study was to compare model results to measured P removal data from several PSM under a range of conditions (P concentrations and RT) and scales ranging from laboratory to field. Materials tested included acid mine drainage residuals (AMDRs), treated and non-treated electric arc furnace (EAF) steel slag at different size fractions, and flue gas desulfurization (FGD) gypsum. Equations for P removal curves and cumulative P removed were not significantly different between predicted and actual values for any of the 23 scenarios examined. However, the model did tend to slightly over-predict cumulative P removal for calcium-based PSMs. The ability of the model to predict P removal for various materials, RTs, and P concentrations in both controlled settings and field structures validate its use in design and quantification of these structures. This ability to predict P removal without constant monitoring is vital to widespread adoption of P removal structures, especially for meeting discharge regulations and nutrient trading programs.

Using a Delphi process to define priorities for prison health research in Canada.

OBJECTIVES: A large number of Canadians spend time in correctional facilities each year, and they are likely to have poor health compared to the general population. Relatively little health research has been conducted in Canada with a focus on people who experience detention or incarceration. We aimed to conduct a Delphi process with key stakeholders to define priorities for research in prison health in Canada for the next 10 years. SETTING: We conducted a Delphi process using an online survey with two rounds in 2014 and 2015. PARTICIPANTS: We invited key stakeholders in prison health research in Canada to participate, which we defined as persons who had published research on prison health in Canada since 1994 and persons in the investigators' professional networks. We invited 143 persons to participate in the first round and 59 participated. We invited 137 persons to participate in the second round and 67 participated. PRIMARY AND SECONDARY OUTCOME MEASURES: Participants suggested topics in the first round, and these topics were collated by investigators. We measured the level of agreement among participants that each collated topic was a priority for prison health research in Canada for the next 10 years, and defined priorities based on the level of agreement. RESULTS: In the first round, participants suggested 71 topics. In the second round, consensus was achieved that a large number of suggested topics were research priorities. Top priorities were diversion and alternatives to incarceration, social and community re-integration, creating healthy environments in prisons, healthcare in custody, continuity of healthcare, substance use disorders and the health of Aboriginal persons in custody. CONCLUSIONS: Generated in an inclusive and systematic process, these findings should inform future research efforts to improve the health and healthcare of people who experience detention and incarceration in Canada.

Little evidence for association between the TGFBR1*6A variant and colorectal cancer: a family-based association study on non-syndromic family members from Australia and Spain.

BACKGROUND: Genome-wide linkage studies have identified the 9q22 chromosomal region as linked with colorectal cancer (CRC) predisposition. A candidate gene in this region is transforming growth factor ß receptor 1 (TGFBR1). Investigation of TGFBR1 has focused on the common genetic variant rs11466445, a short exonic deletion of nine base pairs which results in truncation of a stretch of nine alanine residues to six alanine residues in the gene product. While the six alanine (*6A) allele has been reported to be associated with increased risk of CRC in some population based study groups this association remains the subject of robust debate. To date, reports have been limited to population-based case-control association studies, or case-control studies of CRC families selecting one affected individual per family. No study has yet taken advantage of all the genetic information provided by multiplex CRC families. METHODS: We have tested for an association between rs11466445 and risk of CRC using several family-based statistical tests in a new study group comprising members of non-syndromic high risk CRC families sourced from three familial cancer centres, two in Australia and one in Spain. RESULTS: We report a finding of a nominally significant result using the pedigree-based association test approach (PBAT; p = 0.028), while other family-based tests were non-significant, but with a p-value <; 0.10 in each instance. These other tests included the Generalised Disequilibrium Test (GDT; p = 0.085), parent of origin GDT Generalised Disequilibrium Test (GDT-PO; p = 0.081) and empirical Family-Based Association Test (FBAT; p = 0.096, additive model). Related-person case-control testing using the "More Powerful" Quasi-Likelihood Score Test did not provide any evidence for association (MQLS; p = 0.41). CONCLUSIONS: After conservatively taking into account considerations for multiple hypothesis testing, we find little evidence for an association between the TGFBR1*6A allele and CRC risk in these families. The weak support for an increase in risk in CRC predisposed families is in agreement with recent meta-analyses of case-control studies, which estimate only a modest increase in sporadic CRC risk among 6*A allele carriers.

A panel of genes methylated with high frequency in colorectal cancer.

BACKGROUND: The development of colorectal cancer (CRC) is accompanied by extensive epigenetic changes, including frequent regional hypermethylation particularly of gene promoter regions. Specific genes, including SEPT9, VIM1 and TMEFF2 become methylated in a high fraction of cancers and diagnostic assays for detection of cancer-derived methylated DNA sequences in blood and/or fecal samples are being developed. There is considerable potential for the development of new DNA methylation biomarkers or panels to improve the sensitivity and specificity of current cancer detection tests. METHODS: Combined epigenomic methods - activation of gene expression in CRC cell lines following DNA demethylating treatment, and two novel methods of genome-wide methylation assessment - were used to identify candidate genes methylated in a high fraction of CRCs. Multiplexed amplicon sequencing of PCR products from bisulfite-treated DNA of matched CRC and non-neoplastic tissue as well as healthy donor peripheral blood was performed using Roche 454 sequencing. Levels of DNA methylation in colorectal tissues and blood were determined by quantitative methylation specific PCR (qMSP). RESULTS: Combined analyses identified 42 candidate genes for evaluation as DNA methylation biomarkers. DNA methylation profiles of 24 of these genes were characterised by multiplexed bisulfite-sequencing in ten matched tumor/normal tissue samples; differential methylation in CRC was confirmed for 23 of these genes. qMSP assays were developed for 32 genes, including 15 of the sequenced genes, and used to quantify methylation in tumor, adenoma and non-neoplastic colorectal tissue and from healthy donor peripheral blood. 24 of the 32 genes were methylated in >50% of neoplastic samples, including 11 genes that were methylated in 80% or more CRCs and a similar fraction of adenomas. CONCLUSIONS: This study has characterised a panel of 23 genes that show elevated DNA methylation in >50% of CRC tissue relative to non-neoplastic tissue. Six of these genes (SOX21, SLC6A15, NPY, GRASP, ST8SIA1 and ZSCAN18) show very low methylation in non-neoplastic colorectal tissue and are candidate biomarkers for stool-based assays, while 11 genes (BCAT1, COL4A2, DLX5, FGF5, FOXF1, FOXI2, GRASP, IKZF1, IRF4, SDC2 and SOX21) have very low methylation in peripheral blood DNA and are suitable for further evaluation as blood-based diagnostic markers.

Discovery and validation of molecular biomarkers for colorectal adenomas and cancer with application to blood testing.

BACKGROUND & AIMS: Colorectal cancer incidence and deaths are reduced by the detection and removal of early-stage, treatable neoplasia but we lack proven biomarkers sensitive for both cancer and pre-invasive adenomas. The aims of this study were to determine if adenomas and cancers exhibit characteristic patterns of biomarker expression and to explore whether a tissue-discovered (and validated) biomarker is differentially expressed in the plasma of patients with colorectal adenomas or cancer. METHODS: Candidate RNA biomarkers were identified by oligonucleotide microarray analysis of colorectal specimens (222 normal, 29 adenoma, 161 adenocarcinoma and 50 colitis) and validated in a previously untested cohort of 68 colorectal specimens using a custom-designed oligonucleotide microarray. One validated biomarker, KIAA1199, was assayed using qRT-PCR on plasma extracted RNA from 20 colonoscopy-confirmed healthy controls, 20 patients with adenoma, and 20 with cancer. RESULTS: Genome-wide analysis uncovered reproducible gene expression signatures for both adenomas and cancers compared to controls. 386/489 (79%) of the adenoma and 439/529 (83%) of the adenocarcinoma biomarkers were validated in independent tissues. We also identified genes differentially expressed in adenomas compared to cancer. KIAA1199 was selected for further analysis based on consistent up-regulation in neoplasia, previous studies and its interest as an uncharacterized gene. Plasma KIAA1199 RNA levels were significantly higher in patients with either cancer or adenoma (31/40) compared to neoplasia-free controls (6/20). CONCLUSIONS: Colorectal neoplasia exhibits characteristic patterns of gene expression. KIAA1199 is differentially expressed in neoplastic tissues and KIAA1199 transcripts are more abundant in the plasma of patients with either cancer or adenoma compared to controls.

Evidence of linkage to chromosomes 10p15.3-p15.1, 14q24.3-q31.1 and 9q33.3-q34.3 in non-syndromic colorectal cancer families.

Up to 25% of colorectal cancer (CRC) may be caused by inherited genetic variants that have yet to be identified. Previous genome-wide linkage studies (GWLSs) have identified a new loci postulated to contain novel CRC risk genes amongst affected families carrying no identifiable mutations in any of the known susceptibility genes for familial CRC syndromes. To undertake a new GWLS, we recruited members from 54 non-syndromic families from Australia and Spain where at least two first-degree relatives were affected by CRC. We used single-nucleotide polymorphism arrays to genotype 98 concordant affected relative pairs that were informative for linkage analyses. We tested for genome-wide significance (GWS) for linkage to CRC using a quantile statistic method, and we found that GWS was achieved at the 5% level. Independently, using the PSEUDO gene-dropping algorithm, we also found that GWS for linkage to CRC was achieved (P=0.02). Merlin non-parametric linkage analysis revealed significant linkage to CRC for chromosomal region 10p15.3-p15.1 and suggestive linkage to CRC for regions on 14q and 9q. The 10p15.3-p15.1 has not been reported to be linked to hereditary CRC in previous linkage studies, but this region does harbour the Kruppel-like factor 6 (KLF6) gene that is known to be altered in common CRC. Further studies aimed at localising the responsible genes, and characterising their function will give insight into the factors responsible for susceptibility in such families, and perhaps shed further light on the mechanisms of CRC development.

Reversing the course of forgetting.

Forgetting functions were generated for pigeons in a delayed matching-to-sample task, in which accuracy decreased with increasing retention-interval duration. In baseline training with dark retention intervals, accuracy was high overall. Illumination of the experimental chamber by a houselight during the retention interval impaired performance accuracy by increasing the rate of forgetting. In novel conditions, the houselight was lit at the beginning of a retention interval and then turned off partway through the retention interval. Accuracy was low at the beginning of the retention interval and then increased later in the interval. Thus the course of forgetting was reversed. Such a dissociation of forgetting from the passage of time is consistent with an interference account in which attention or stimulus control switches between the remembering task and extraneous events.

Reversing the signaled magnitude effect in delayed matching to sample: delay-specific remembering.

Pigeons performed a delayed matching-to-sample task in which large or small reinforcers for correct remembering were signaled during the retention interval. Accuracy was low when small reinforcers were signaled, and high when large reinforcers were signaled (the signaled magnitude effect). When the reinforcer-size cue was switched from small to large partway through the retention interval, accuracy accordingly changed from low to high. The opposite happened when the cue was switched from large to small. This dissociation of forgetting from the passage of time raises the possibility that remembering is delay-specific. The reversal of the signaled magnitude effect during the retention interval is consistent with an attentional account in which the stimulus control of remembering is influenced by extraneous events.

Colorectal Neoplasia Differentially Expressed (CRNDE), a Novel Gene with Elevated Expression in Colorectal Adenomas and Adenocarcinomas.

An uncharacterized gene locus (Chr16:hCG_1815491), now named colorectal neoplasia differentially expressed (gene symbol CRNDE), is activated early in colorectal neoplasia. The locus is unrelated to any known protein-coding gene. Microarray analysis of 454 tissue specimens (discovery) and 68 previously untested specimens (validation) showed elevated expression of CRNDE in >90% of colorectal adenomas and adenocarcinomas. These findings were confirmed and extended by exon microarray studies and RT-PCR assays. CRNDE transcription start sites were identified in CaCo2 and HCT116 cells by 5'-RACE. The major transcript isoforms in colorectal cancer (CRC) cell lines and colorectal tissue are CRNDE-a, -b, -d, -e, -f, -h, and -j. Except for CRNDE-d, the known CRNDE splice variants are upregulated in neoplastic colorectal tissue; expression levels for CRNDE-h alone demonstrate a sensitivity of 95% and specificity of 96% for adenoma versus normal tissue. A quantitative RT-PCR assay measuring CRNDE-h RNA levels in plasma was (with a threshold of 2(-ΔCt) = 2.8) positive for 13 of 15 CRC patients (87%) but only 1 of 15 healthy individuals (7%). We conclude that individual CRNDE transcripts show promise as tissue and plasma biomarkers, potentially exhibiting high sensitivity and specificity for colorectal adenomas and cancers.

Reinforcer probability, reinforcer magnitude, and the reinforcement context for remembering.

Traditional theories of delayed matching-to-sample performance do not predict that accuracy will improve when absolute levels of reinforcement are increased. This prediction emerges only when reinforcement context is considered (J. A. Nevin, M. Davison, A. L. Odum, & T. A. Shahan, 2007). To provide quantitative data, the authors factorially manipulated between conditions the probability and duration of reinforcement for correct choices by pigeons. In Experiment 1, increasing the value of either variable improved initial discriminability of the forgetting functions, but did not affect the rate of forgetting. In Experiment 2, initial discriminability covaried with changes in choice immediacy and trial completion rate, suggesting a relationship with response strength consistent with Nevin et al.'s behavioral momentum model. Adding reinforcement context to K. G. White and J. T. Wixted's (1999) model also generates predictions consistent with the present experiments and with the effects of manipulating extraneous reinforcement. The inclusion of reinforcement context thus improves predictions of delayed matching-to-sample performance.