Search

Abstract Background The application and better understanding of traditional and new breast tumor biomarkers and prognostic factors are increasing due to the fact that they are able to identify individuals at high risk of breast cancer, who may benefit from preventive interventions. Also, biomarkers can make possible for physicians to design an individualized treatment for each patient. Previous studies showed that trace elements (TEs) determined by X-Ray Fluorescence (XRF) techniques are found in significantly higher concentrations in neoplastic breast tissues (malignant and benign) when compared with normal tissues. The aim of this work was to evaluate the potential of TEs, determined by the use of the Energy Dispersive X-Ray Fluorescence (EDXRF) technique, as biomarkers and prognostic factors in breast cancer. Methods By using EDXRF, we determined Ca, Fe, Cu, and Zn trace elements concentrations in 106 samples of normal and breast cancer tissues. Cut-off values for each TE were determined through Receiver Operating Characteristic (ROC) analysis from the TEs distributions. These values were used to set the positive or negative expression. This expression was subsequently correlated with clinical prognostic factors through Fisher’s exact test and chi-square test. Kaplan Meier survival curves were also evaluated to assess the effect of the expression of TEs in the overall patient survival. Results Concentrations of TEs are higher in neoplastic tissues (malignant and benign) when compared with normal tissues. Results from ROC analysis showed that TEs can be considered a tumor biomarker because, after establishing a cut-off value, it was possible to classify different tissues as normal or neoplastic, as well as different types of cancer. The expression of TEs was found statistically correlated with age and menstrual status. The survival curves estimated by the Kaplan-Meier method showed that patients with positive expression for Cu presented a poor overall survival (p Conclusions This study suggests that TEs expression has a great potential of application as a tumor biomarker, once it was revealed to be an effective tool to distinguish different types of breast tissues and to identify the difference between malignant and benign tumors. The expressions of all TEs were found statistically correlated with well-known prognostic factors for breast cancer. The element copper also showed statistical correlation with overall survival.

Abstract Background Cancer stem cell (CSC) hypothesis postulates that tumors are maintained by a self-renewing CSC population that is also capable of differentiating into non-self-renewing cell populations that constitute the bulk of tumor. Stem cells renewal and differentiation can be directly influenced by the oxygen levels of determined tissues, probably by the reduction of oxidative DNA damage in hypoxic regions, thus leading to a friendlier microenvironment, regarding to clonal expansion and for resistance to chemotherapeutic regimens. Furthermore, there have been strong data indicating a pivotal role of hypoxic niche in cancer stem cells development. There are evidence that hypoxia could drive the maintenance of CSC, via HIF-1α expression, but it still to be determined whether hypoxia markers are expressed in breast tumors presenting CD44+CD24-/low immunophenotype. Methods Immunohistochemical analysis of CD44+CD24-/low expression and its relationship with hypoxia markers and clinical outcome were evaluated in 253 samples of breast ductal carcinomas. Double-immunolabeling was performed using EnVision Doublestain System (Dako, Carpinteria, CA, USA). Slides were then scanned into high-resolution images using Aperio ScanScope XT and then, visualized in the software Image Scope (Aperio, Vista, CA, USA). Results In univariate analysis, CD44+CD24-/low expression showed association with death due to breast cancer (p = 0.035). Breast tumors expressing CD44+CD24-/low immunophenotype showed relationship with HIF-1α (p = 0.039) and negativity for HER-2 (p = 0.013). Conclusion Considering that there are strong evidences that the fraction of a tumour considered to be cancer stem cells is plastic depending upon microenvironmental signals, our findings provide further evidence that hypoxia might be related to the worse prognosis found in CD44+CD24-/low positive breast tumors.

Background: Although behavioral mechanisms in the association among depression, anxiety, and cancer are plausible, few studies have empirically studied mediation by health behaviors. We aimed to examine the mediating role of several health behaviors in the associations among depression, anxiety, and the incidence of various cancer types (overall, breast, prostate, lung, colorectal, smoking-related, and alcohol-related cancers)., Methods: Two-stage individual participant data meta-analyses were performed based on 18 cohorts within the Psychosocial Factors and Cancer Incidence consortium that had a measure of depression or anxiety ( N = 319 613, cancer incidence = 25 803). Health behaviors included smoking, physical inactivity, alcohol use, body mass index (BMI), sedentary behavior, and sleep duration and quality. In stage one, path-specific regression estimates were obtained in each cohort. In stage two, cohort-specific estimates were pooled using random-effects multivariate meta-analysis, and natural indirect effects (i.e. mediating effects) were calculated as hazard ratios (HRs)., Results: Smoking (HRs range 1.04-1.10) and physical inactivity (HRs range 1.01-1.02) significantly mediated the associations among depression, anxiety, and lung cancer. Smoking was also a mediator for smoking-related cancers (HRs range 1.03-1.06). There was mediation by health behaviors, especially smoking, physical inactivity, alcohol use, and a higher BMI, in the associations among depression, anxiety, and overall cancer or other types of cancer, but effects were small (HRs generally below 1.01)., Conclusions: Smoking constitutes a mediating pathway linking depression and anxiety to lung cancer and smoking-related cancers. Our findings underline the importance of smoking cessation interventions for persons with depression or anxiety.

Depression, anxiety and other psychosocial factors are hypothesized to be involved in cancer development. We examined whether psychosocial factors interact with or modify the effects of health behaviors, such as smoking and alcohol use, in relation to cancer incidence. Two-stage individual participant data meta-analyses were performed based on 22 cohorts of the PSYchosocial factors and CAncer (PSY-CA) study. We examined nine psychosocial factors (depression diagnosis, depression symptoms, anxiety diagnosis, anxiety symptoms, perceived social support, loss events, general distress, neuroticism, relationship status), seven health behaviors/behavior-related factors (smoking, alcohol use, physical activity, body mass index, sedentary behavior, sleep quality, sleep duration) and seven cancer outcomes (overall cancer, smoking-related, alcohol-related, breast, lung, prostate, colorectal). Effects of the psychosocial factor, health behavior and their product term on cancer incidence were estimated using Cox regression. We pooled cohort-specific estimates using multivariate random-effects meta-analyses. Additive and multiplicative interaction/effect modification was examined. This study involved 437,827 participants, 36,961 incident cancer diagnoses, and 4,749,481 person years of follow-up. Out of 744 combinations of psychosocial factors, health behaviors, and cancer outcomes, we found no evidence of interaction. Effect modification was found for some combinations, but there were no clear patterns for any particular factors or outcomes involved. In this first large study to systematically examine potential interaction and effect modification, we found no evidence for psychosocial factors to interact with or modify health behaviors in relation to cancer incidence. The behavioral risk profile for cancer incidence is similar in people with and without psychosocial stress., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Depression and anxiety have long been hypothesized to be related to an increased cancer risk. Despite the great amount of research that has been conducted, findings are inconclusive. To provide a stronger basis for addressing the associations between depression, anxiety, and the incidence of various cancer types (overall, breast, lung, prostate, colorectal, alcohol-related, and smoking-related cancers), individual participant data (IPD) meta-analyses were performed within the Psychosocial Factors and Cancer Incidence (PSY-CA) consortium., Methods: The PSY-CA consortium includes data from 18 cohorts with measures of depression or anxiety (up to N = 319,613; cancer incidences, 25,803; person-years of follow-up, 3,254,714). Both symptoms and a diagnosis of depression and anxiety were examined as predictors of future cancer risk. Two-stage IPD meta-analyses were run, first by using Cox regression models in each cohort (stage 1), and then by aggregating the results in random-effects meta-analyses (stage 2)., Results: No associations were found between depression or anxiety and overall, breast, prostate, colorectal, and alcohol-related cancers. Depression and anxiety (symptoms and diagnoses) were associated with the incidence of lung cancer and smoking-related cancers (hazard ratios [HRs], 1.06-1.60). However, these associations were substantially attenuated when additionally adjusting for known risk factors including smoking, alcohol use, and body mass index (HRs, 1.04-1.23)., Conclusions: Depression and anxiety are not related to increased risk for most cancer outcomes, except for lung and smoking-related cancers. This study shows that key covariates are likely to explain the relationship between depression, anxiety, and lung and smoking-related cancers. PREREGISTRATION NUMBER: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=157677., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Single-cell RNA sequencing can reveal valuable insights into cellular heterogeneity within tumour microenvironments (TMEs), paving the way for a deep understanding of cellular mechanisms contributing to cancer. However, high heterogeneity among the same cancer types and low transcriptomic variation in immune cell subsets present challenges for accurate, high-resolution confirmation of cells' identities. Here we present scATOMIC; a modular annotation tool for malignant and non-malignant cells. We trained scATOMIC on >300,000 cancer, immune, and stromal cells defining a pan-cancer reference across 19 common cancers and employ a hierarchical approach, outperforming current classification methods. We extensively confirm scATOMIC's accuracy on 225 tumour biopsies encompassing >350,000 cancer and a variety of TME cells. Lastly, we demonstrate scATOMIC's practical significance to accurately subset breast cancers into clinically relevant subtypes and predict tumours' primary origin across metastatic cancers. Our approach represents a broadly applicable strategy to analyse multicellular cancer TMEs., (© 2023. The Author(s).)

How the genetic composition of a population changes through stochastic processes, such as genetic drift, in combination with deterministic processes, such as selection, is critical to understanding how phenotypes vary in space and time. Here, we show how evolutionary forces affecting selection, including recombination and effective population size, drive genomic patterns of allele-specific expression (ASE). Integrating tissue-specific genotypic and transcriptomic data from 1500 individuals from two different cohorts, we demonstrate that ASE is less often observed in regions of low recombination, and loci in high or normal recombination regions are more efficient at using ASE to underexpress harmful mutations. By tracking genetic ancestry, we discriminate between ASE variability due to past demographic effects, including subsequent bottlenecks, versus local environment. We observe that ASE is not randomly distributed along the genome and that population parameters influencing the efficacy of natural selection alter ASE levels genome wide.

Age-related clonal hematopoiesis (ARCH) is characterized by age-associated accumulation of somatic mutations in hematopoietic stem cells (HSCs) or their pluripotent descendants. HSCs harboring driver mutations will be positively selected and cells carrying these mutations will rise in frequency. While ARCH is a known risk factor for blood malignancies, such as Acute Myeloid Leukemia (AML), why some people who harbor ARCH driver mutations do not progress to AML remains unclear. Here, we model the interaction of positive and negative selection in deeply sequenced blood samples from individuals who subsequently progressed to AML, compared to healthy controls, using deep learning and population genetics. Our modeling allows us to discriminate amongst evolutionary classes with high accuracy and captures signatures of purifying selection in most individuals. Purifying selection, acting on benign or mildly damaging passenger mutations, appears to play a critical role in preventing disease-predisposing clones from rising to dominance and is associated with longer disease-free survival. Through exploring a range of evolutionary models, we show how different classes of selection shape clonal dynamics and health outcomes thus enabling us to better identify individuals at a high risk of malignancy., (© 2021. The Author(s).)

Tests for variance or scale effects due to covariates are used in many areas and recently, in genomic and genetic association studies. We study score tests based on location-scale models with arbitrary error distributions that allow incorporation of additional adjustment covariates. Tests based on Gaussian and Laplacian double generalized linear models are examined in some detail. Numerical properties of the tests under Gaussian and other error distributions are examined. Our results show that the use of model-based asymptotic distributions with score tests for scale effects does not control type 1 error well in many settings of practical relevance. We consider simple statistics based on permutation distribution approximations, which correspond to well-known statistics derived by another approach. They are shown to give good type 1 error control under different error distributions and under covariate distribution imbalance. The methods are illustrated through a differential gene expression analysis involving breast cancer tumor samples., (© 2021 John Wiley & Sons Ltd.)

Cystic Fibrosis (CF) exhibits morbidity in several organs, including progressive lung disease in all patients and intestinal obstruction at birth (meconium ileus) in ~15%. Individuals with the same causal CFTR mutations show variable disease presentation which is partly attributed to modifier genes. With >6,500 participants from the International CF Gene Modifier Consortium, genome-wide association investigation identified a new modifier locus for meconium ileus encompassing ATP12A on chromosome 13 (min p = 3.83x10(-10)); replicated loci encompassing SLC6A14 on chromosome X and SLC26A9 on chromosome 1, (min p<2.2x10(-16), 2.81x10(-11), respectively); and replicated a suggestive locus on chromosome 7 near PRSS1 (min p = 2.55x10(-7)). PRSS1 is exclusively expressed in the exocrine pancreas and was previously associated with non-CF pancreatitis with functional characterization demonstrating impact on PRSS1 gene expression. We thus asked whether the other meconium ileus modifier loci impact gene expression and in which organ. We developed and applied a colocalization framework called the Simple Sum (SS) that integrates regulatory and genetic association information, and also contrasts colocalization evidence across tissues or genes. The associated modifier loci colocalized with expression quantitative trait loci (eQTLs) for ATP12A (p = 3.35x10(-8)), SLC6A14 (p = 1.12x10(-10)) and SLC26A9 (p = 4.48x10(-5)) in the pancreas, even though meconium ileus manifests in the intestine. The meconium ileus susceptibility locus on chromosome X appeared shifted in location from a previously identified locus for CF lung disease severity. Using the SS we integrated the lung disease association locus with eQTLs from nasal epithelia of 63 CF participants and demonstrated evidence of colocalization with airway-specific regulation of SLC6A14 (p = 2.3x10(-4)). Cystic Fibrosis is realizing the promise of personalized medicine, and identification of the contributing organ and understanding of tissue specificity for a gene modifier is essential for the next phase of personalizing therapeutic strategies., Competing Interests: The authors have declared that no competing interests exist.

The binding of PRDM9 to chromatin is a key step in the induction of DNA double-strand breaks associated with meiotic recombination hotspots; it is normally expressed solely in germ cells. We interrogated 1879 cancer samples in 39 different cancer types and found that PRDM9 is unexpectedly expressed in 20% of these tumors even after stringent gene homology correction. The expression levels of PRDM9 in tumors are significantly higher than those found in healthy neighboring tissues and in healthy nongerm tissue databases. Recurrently mutated regions located within 5 Mb of the PRDM9 loci, as well as differentially expressed genes in meiotic pathways, correlate with PRDM9 expression. In samples with aberrant PRDM9 expression, structural variant breakpoints frequently neighbor the DNA motif recognized by PRDM9, and there is an enrichment of structural variants at sites of known meiotic PRDM9 activity. This study is the first to provide evidence of an association between aberrant expression of the meiosis-specific gene PRDM9 with genomic instability in cancer., (© 2018 Ang Houle et al.; Published by Cold Spring Harbor Laboratory Press.)

The incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure 1 . The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukaemic haematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion 2,3 . However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis (ARCH) 4-8 . Here we use deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH. We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis (pre-AML group), together with 414 unselected age- and gender-matched individuals (control group). Pre-AML cases were distinct from controls and had more mutations per sample, higher variant allele frequencies, indicating greater clonal expansion, and showed enrichment of mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival; this model was validated in an independent cohort of 29 pre-AML cases and 262 controls. Because AML is rare, we also developed an AML predictive model using a large electronic health record database that identified individuals at greater risk. Collectively our findings provide proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation. This could in future enable earlier detection and monitoring, and may help to inform intervention.

Uncovering the interaction between genomes and the environment is a principal challenge of modern genomics and preventive medicine. While theoretical models are well defined, little is known of the G × E interactions in humans. We used an integrative approach to comprehensively assess the interactions between 1.6 million data points, encompassing a range of environmental exposures, health, and gene expression levels, coupled with whole-genome genetic variation. From ∼1000 individuals of a founder population in Quebec, we reveal a substantial impact of the environment on the transcriptome and clinical endophenotypes, overpowering that of genetic ancestry. Air pollution impacts gene expression and pathways affecting cardio-metabolic and respiratory traits, when controlling for genetic ancestry. Finally, we capture four expression quantitative trait loci that interact with the environment (air pollution). Our findings demonstrate how the local environment directly affects disease risk phenotypes and that genetic variation, including less common variants, can modulate individual's response to environmental challenges.

We generalize Levene's test for variance (scale) heterogeneity between k groups for more complex data, when there are sample correlation and group membership uncertainty. Following a two-stage regression framework, we show that least absolute deviation regression must be used in the stage 1 analysis to ensure a correct asymptotic χk-12/(k-1) distribution of the generalized scale (gS) test statistic. We then show that the proposed gS test is independent of the generalized location test, under the joint null hypothesis of no mean and no variance heterogeneity. Consequently, we generalize the recently proposed joint location-scale (gJLS) test, valuable in settings where there is an interaction effect but one interacting variable is not available. We evaluate the proposed method via an extensive simulation study and two genetic association application studies., (© 2017 The Authors Biometrics published by Wiley Periodicals, Inc. on behalf of International Biometric Society.)

Cystic fibrosis is realizing the promise of personalized medicine. Recent advances in drug development that target the causal CFTR directly result in lung function improvement, but variability in response is demanding better prediction of outcomes to improve management decisions. The genetic modifier SLC26A9 contributes to disease severity in the CF pancreas and intestine at birth and here we assess its relationship with disease severity and therapeutic response in the airways. SLC26A9 association with lung disease was assessed in individuals from the Canadian and French CF Gene Modifier consortia with CFTR-gating mutations and in those homozygous for the common Phe508del mutation. Variability in response to a CFTR-directed therapy attributed to SLC26A9 genotype was assessed in Canadian patients with gating mutations. A primary airway model system determined if SLC26A9 shows modification of Phe508del CFTR function upon treatment with a CFTR corrector. In those with gating mutations that retain cell surface-localized CFTR we show that SLC26A9 modifies lung function while this is not the case in individuals homozygous for Phe508del where cell surface expression is lacking. Treatment response to ivacaftor, which aims to improve CFTR-channel opening probability in patients with gating mutations, shows substantial variability in response, 28% of which can be explained by rs7512462 in SLC26A9 (P = 0.0006). When homozygous Phe508del primary bronchial cells are treated to restore surface CFTR, SLC26A9 likewise modifies treatment response (P = 0.02). Our findings indicate that SLC26A9 airway modification requires CFTR at the cell surface, and that a common variant in SLC26A9 may predict response to CFTR-directed therapeutics.

Gene-based, pathway, and other multivariate association methods are motivated by the possibility of GxG and GxE interactions; however, accounting for such interactions is limited by the challenges associated with adequate modeling information. Here we propose an easy-to-implement joint location-scale (JLS) association testing framework for single-variant and multivariate analysis that accounts for interactions without explicitly modeling them. We apply the JLS method to a gene-set analysis of cystic fibrosis (CF) lung disease, which is influenced by multiple environmental and genetic factors. We identify and replicate an association between the constituents of the apical plasma membrane and CF lung disease (p = 0.0099 and p = 0.0180, respectively) and highlight a role for the SLC9A3-SLC9A3R1/2-EZR complex in contributing to CF lung disease. Many association studies could benefit from re-analysis with the JLS method that leverages complex genetic architecture for SNP, gene, and pathway identification. Analytical verification, simulation, and additional proof-of-principle applications support our approach., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To test the hypothesis that multiple constituents of the apical plasma membrane residing alongside the causal cystic fibrosis (CF) transmembrane conductance regulator protein, including known CF modifiers SLC26A9, SLC6A14, and SLC9A3, would be associated with prenatal exocrine pancreatic damage as measured by newborn screened (NBS) immunoreactive trypsinogen (IRT) levels., Study Design: NBS IRT measures and genome-wide genotype data were available on 111 subjects from Colorado, 37 subjects from Wisconsin, and 80 subjects from France. Multiple linear regression was used to determine whether any of 8 single nucleotide polymorphisms (SNPs) in SLC26A9, SLC6A14, and SLC9A3 were associated with IRT and whether other constituents of the apical plasma membrane contributed to IRT., Results: In the Colorado sample, 3 SLC26A9 SNPs were associated with NBS IRT (min P=1.16×10(-3); rs7512462), but no SLC6A14 or SLC9A3 SNPs were associated (P>.05). The rs7512462 association replicated in the Wisconsin sample (P=.03) but not in the French sample (P=.76). Furthermore, rs7512462 was the top-ranked apical membrane constituent in the combined Colorado and Wisconsin sample., Conclusions: NBS IRT is a biomarker of prenatal exocrine pancreatic disease in patients with CF, and a SNP in SLC26A9 accounts for significant IRT variability. This work suggests SLC26A9 as a potential therapeutic target to ameliorate exocrine pancreatic disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective : We assessed the change in attitudes, knowledge, and perspectives of medical students towards chiropractic after a 1-hour educational intervention. Methods : A mixed-methods approach was used with a 52-item cross-sectional paper survey and 1 focus group of third-year medical students. The views of these medical students towards chiropractic were assessed previously in their second-year of medical school. ANOVA and the Wilcoxon rank-sum test were used to assess between-group differences between the medical students' views before and after the educational intervention. The constant comparative method for analyzing qualitative data was used to identify emergent themes from the focus group transcript. Results : Of 112 third-year medical students, 58 completed the survey (51.7% response rate). The focus group consisted of 6 medical students. Self-reported understanding of chiropractic and number of attitude-positive responses were significantly higher in the group after the educational session. The average number of correct responses assessing knowledge on chiropractic also was significantly higher. Focus group themes were that medical students wanted exposure to chiropractic in clinical settings, had negative attitudes towards chiropractic formed from hidden curriculum, had concerns regarding evidence and safety of chiropractic, and thought that timing of the session on chiropractic was too late in the curriculum. Conclusions : The attitudes and knowledge of medical students towards chiropractic improved immediately after a 1-hour educational intervention. Formally educating medical students on chiropractic may help minimize hidden curriculum issues regarding chiropractic, as identified by the medical students, and facilitate collaboration between medical and chiropractic providers.

Circulating immunoreactive trypsinogen (IRT), a biomarker of exocrine pancreatic disease in cystic fibrosis (CF), is elevated in most CF newborns. In those with severe CF transmembrane conductance regulator (CFTR) genotypes, IRT declines rapidly in the first years of life, reflecting progressive pancreatic damage. Consistent with this progression, a less elevated newborn IRT measure would reflect more severe pancreatic disease, including compromised islet compartments, and potentially increased risk of CF-related diabetes (CFRD). We show in two independent CF populations that a lower newborn IRT estimate is associated with higher CFRD risk among individuals with severe CFTR genotypes, and we provide evidence to support a causal relationship. Increased loge(IRT) at birth was associated with decreased CFRD risk in Canadian and Colorado samples (hazard ratio 0.30 [95% CI 0.15-0.61] and 0.39 [0.18-0.81], respectively). Using Mendelian randomization with the SLC26A9 rs7512462 genotype as an instrumental variable since it is known to be associated with IRT birth levels in the CF population, we provide evidence to support a causal contribution of exocrine pancreatic status on CFRD risk. Our findings suggest CFRD risk could be predicted in early life and that maintained ductal fluid flow in the exocrine pancreas could delay the onset of CFRD., (© 2014 by the American Diabetes Association.)

Background: As health care has increased in complexity and health care teams have been offered as a solution, so too is there an increased need for stronger interprofessional collaboration. However the intraprofessional factions that exist within every profession challenge interprofessional communication through contrary paradigms. As a contender in the conservative spinal health care market, factions within chiropractic that result in unorthodox practice behaviours may compromise interprofessional relations and that profession's progress toward institutionalization. The purpose of this investigation was to quantify the professional stratification among Canadian chiropractic practitioners and evaluate the practice perceptions of those factions., Methods: A stratified random sample of 740 Canadian chiropractors was surveyed to determine faction membership and how professional stratification could be related to views that could be considered unorthodox to current evidence-based care and guidelines. Stratification in practice behaviours is a stated concern of mainstream medicine when considering interprofessional referrals., Results: Of 740 deliverable questionnaires, 503 were returned for a response rate of 68%. Less than 20% of chiropractors (18.8%) were aligned with a predefined unorthodox perspective of the conditions they treat. Prediction models suggest that unorthodox perceptions of health practice related to treatment choices, x-ray use and vaccinations were strongly associated with unorthodox group membership (X(2) =13.4, p = 0.0002)., Conclusion: Chiropractors holding unorthodox views may be identified based on response to specific beliefs that appear to align with unorthodox health practices. Despite continued concerns by mainstream medicine, only a minority of the profession has retained a perspective in contrast to current scientific paradigms. Understanding the profession's factions is important to the anticipation of care delivery when considering interprofessional referral.

The existence of pleiotropy in disorders with multi-organ involvement can suggest therapeutic targets that could ameliorate overall disease severity. Here we assessed pleiotropy of modifier genes in cystic fibrosis (CF). CF, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, affects the lungs, liver, pancreas and intestines. However, modifier genes contribute to variable disease severity across affected organs, even in individuals with the same CFTR genotype. We sought to determine whether SLC26A9, SLC9A3 and SLC6A14, that contribute to meconium ileus in CF, are pleiotropic for other early-affecting CF co-morbidities. In the Canadian CF population, we assessed evidence for pleiotropic effects on (1) pediatric lung disease severity (n = 815), (2) age at first acquisition of Pseudomonas aeruginosa (P. aeruginosa) (n = 730), and (3) prenatal pancreatic damage measured by immunoreactive trypsinogen (n = 126). A multiple-phenotype analytic strategy assessed evidence for pleiotropy in the presence of phenotypic correlation. We required the same alleles to be associated with detrimental effects. SLC26A9 was pleiotropic for meconium ileus and pancreatic damage (p = 0.002 at rs7512462), SLC9A3 for meconium ileus and lung disease (p = 1.5 × 10(-6) at rs17563161), and SLC6A14 for meconium ileus and both lung disease and age at first P. aeruginosa infection (p = 0.0002 and p = 0.006 at rs3788766, respectively). The meconium ileus risk alleles in SLC26A9, SLC9A3 and SLC6A14 are pleiotropic, increasing risk for other early CF co-morbidities. Furthermore, co-morbidities affecting the same organ tended to associate with the same genes. The existence of pleiotropy within this single disorder suggests that complementary therapeutic strategies to augment solute transport will benefit multiple CF-associated tissues.

Objective: Participants in clinical trials of spinal manipulation have not been rigorously blinded to group assignment. This study reports on secondary analyses of the retention of participant blinding beyond the immediate posttreatment time frame following a single-session, randomized clinical study. A novel control cervical manipulation procedure that has previously been shown to be therapeutically inert was contrasted with a typical manipulation procedure., Methods: A randomized clinical study of a single session of typical vs sham-control manipulation in patients with chronic neck pain was conducted. Findings of self-reported group registration at 24 to 48 hours posttreatment were computed. The Blinding Index (BI) of Bang et al was then applied to both the immediate and post-24- to 48-hour results., Results: Twenty-four to 48 hours after treatment, 94% and 22% of participants in the typical and control groups, respectively, correctly identified their group assignment. When analyzed with the BI of Bang et al, the immediate posttreatment BI for the group receiving a typical manipulation was 0.22 (95% confidence interval [CI], -0.03 to 0.47); for the group receiving a control manipulation, it was 0.19 (95% CI, -0.06 to 0.43). The BI at post-24 hours was as follows: typical = 0.75 (95% CI, 0.59-0.91) and control = -0.34 (95% CI, -0.58 to -0.11)., Conclusions: This study found that the novel sham-control cervical manipulation procedure may be effective in blinding sham group allocation up to 48 hours posttreatment. It appears that, at 48 hours posttreatment, the modified form of the typical cervical manipulation was not. The sham-control procedure appears to be a promising procedure for future clinical trials., (© 2013. Published by National University of Health Sciences All rights reserved.)

Background: Several risk factors exist for the development of low back pain, including prolonged sitting and flexed spinal curvature. Several investigators have studied lumbar support devices and spinal curvatures in sitting, however few have investigated a pain population and reported a quantitative measure of comfort. The purpose of the current project was to determine whether a lumbar support pillow, outfitted with a cut-out to accommodate the bulk of posterior pelvic soft tissue volume, is more effective than a standard chair in promoting a neutral spinal posture and improving subjective and objective measures of comfort in healthy individuals and patients with low back pain., Methods: Twenty eight male participants with and without a history of low back pain sat in a standard office chair and in a chair with the lumbar support pillow for 30 minutes. Lumbar and thoracolumbar postures were measured through electromagnetic markers. Comfort was determined based on the least squares radius of centre of pressure shifting, measured at the buttock-chair interface as well as reported discomfort through visual analog scales. Chair support effects were assessed through ANOVA methods. The study was approved by the Canadian Memorial Chiropractic College research ethics board., Results: There was a main effect of condition on lumbar posture (p = 0.006) and thoracolumbar posture (p = 0.014). In the lumbar region, the support and standard chair differed by 2.88° (95% CI; 1.01-4.75), with the lumbar support being closer to neutral than the standard chair. In the thoracolumbar region, the support and standard chair differed by -2.42° (95% CI; -4.22 to -0.62), with the standard chair being closer to neutral than the support device. The centre of pressure measure was significantly improved with the pillow (p = 0.017), however there were no subjective changes in comfort., Conclusions: A lumbar support pillow with a cut-out for the posterior pelvic tissues improved an objective measure of comfort in healthy individuals and patients with low back pain. Lumbar flattening was decreased and thoracolumbar curvature was increased. However, angular changes were small and future work is required to determine clinical relevance over the long term., Trial Registration: ClinicalTrials.gov, NCT00754585.

Objective: To assess second-year medical students' views on chiropractic., Methods: A three-step triangulation approach was designed, comprising a 53-item survey, nine key informant interviews and one focus group of 8 subjects. ANOVA was used to assess attitude-response survey totals over grouping variables. Constant comparison method and NVivo was used for thematic analysis., Results: 112 medical students completed the survey (50% response rate). Subjects reporting no previous chiropractic experience/exposure or interest in learning about chiropractic were significantly more attitude-negative towards chiropractic. Thematically, medical students viewed chiropractic as an increasingly evidence-based complementary therapy for low back/chronic pain, but based views on indirect sources. Within formal curriculum, they wanted to learn about clinical conditions and benefits/risks related to treatment, as greater understanding was needed for future patient referrals., Conclusion: The results highlight the importance of exposure to chiropractic within the formal medical curriculum to help foster future collaboration between these two professions.

Purpose: The influence of self-rated disability and fear-avoidance beliefs on whiplash sufferers in their performance of active ranges of motion has not been studied well. We undertook a cross-sectional study to determine this., Methods: Chronic whiplash subjects completed a standard clinical examination. They completed the Neck Disability Index (NDI), the Tampa Scale for Kinesiophobia (TSK) and pain visual analog scale (VAS). Active ranges of motion (goniometer) and cervical nonorganic simulation signs (C-NOSS) were obtained by the examiner. Univariate and multivariable analyses were conducted on these scores., Results: Sixty-four subjects (37 female) with a mean age of 41.4 (SD 16.1) years completed all scores. NDI, pain VAS and C-NOSS correlated significantly with ROM. In a multivariable model, only the NDI score contributed significantly to the variance of the ROM scores (14%)., Conclusion: As chronic whiplash sufferers perform ROM in a clinical examination, these ranges are importantly influenced by their self-perceived disability. Cervical nonorganic simulation signs can be helpful in distinguishing high from very high levels of disability and motion restriction. The lack of correlation with the TSK may present a challenge to the Fear Avoidance Model in whiplash. Implications for Rehabilitation Self-ratings of disability in chronic whiplash sufferers are influenced by their fear-avoidance beliefs. While self-ratings of disability are known to predict chronicity of whiplash, there is less known about how these ratings affect impairment assessment during recovery. This study shows that self-ratings of disability influence the presentation of impairment by chronic whiplash sufferers with respect to their ranges of neck motion. Signs of nonorganic behavior also influence ranges of motion and self-ratings of disability. These findings should be incorporated into the interpretation of impairment findings in chronic whiplash sufferers in order to improve management.

To date, only a few studies have evaluated the effect of physical activity on PWVcf in the elderly. In the current study, 21 community-dwelling women, with a mean age of 68.19±5.72 years and a mean BMI of 28.63±4.69 kg m(-2), participated in moderate physical activity sessions for 1 h per day and 2 days each week under the supervision of a qualified physical education instructor for a total of 24 weeks. At the beginning of the study, at 3 months and at 6 months, the study participants' body weight, waist circumference, sagittal abdominal diameter (SAD) and body composition by dual energy X-ray absorptiometry (DEXA) were recorded along with the participants' Physical Activity Scale for the Elderly questionnaire. Total low-density-lipoprotein and high-density lipoprotein cholesterol; triglycerides (TGs) and HbA1c; blood pressure (BP); and arterial stiffness, as determined by carotid-femoral and carotid-radial pulse wave velocity (PWVcf, PWVcr), were also assessed. During the follow-up period, the waist and SAD significantly decreased, whereas fat-free mass, BMI and weight did not decrease. A significant decline in TGs was observed. A significant decline in PWVcf, even after adjusting for mean arterial pressure, heart rate triglycerides and waist diameter changes, was observed. In a sub-analysis that examined the effect of physical activity separately in the hypertensive and normotensive subjects, we observed a significant decline in PWVcf in the hypertensive subjects and a nonsignificant tendency in the normotensive subjects. The data showed an association between light aerobic physical activity in the elderly and decreased PWVcf, even after adjusting for changes in systolic BP (SBP), TGs and central adiposity. These results suggest a beneficial effect of moderate physical activity on subclinical vascular damage, particularly in hypertensive subjects.

Objective: The purposes of this study were to survey Council on Chiropractic Education-accredited chiropractic colleges in North America and to describe curricular details on the teaching of bioethics., Methods: A custom-designed survey was sent to chiropractic colleges. Total number of contact hours, whether the ethics was a stand-alone course or integrated elsewhere, type of instructor, and if there was a required or recommended course text were queried., Results: Of 19 surveys sent by mail, 15 surveys were returned. The average time in ethics instruction was 18.7 hours including lecture format, small group tutorial, and self-study. Chiropractic ethics education includes 8 areas of content (boundaries, law and jurisprudence, professionalism, basic ethic tenets/principles, ethical codes of conduct, prevention of financial and of sexual abuse, and resolving an ethical dilemma). Some colleges include content taught to students under the domain of law and jurisprudence., Conclusion: The results of this survey indicate that there are opportunities to further develop the educational ethics program at Council on Chiropractic Education-accredited colleges. All colleges currently offer bioethics teaching. An expanded role for this content is recommended so as to offer optimal benefit for students and practitioners., (Copyright © 2012 National University of Health Sciences. Published by Mosby, Inc. All rights reserved.)

Objective: The purpose of this study was to determine the correlation between cerebral perfusion levels, Neck Disability Index (NDI) scores, and spinal joint fixations in patients with neck pain., Methods: Forty-five adult patients (29 were female) with chronic neck/upper thoracic pain during exacerbation were studied. The subjects were grouped according to NDI scores: mild, moderate, and severe. The number of painful/blocked segments in the cervical and upper thoracic spine and costovertebral joints, pain intensity using the visual analog scale, and regional cerebral blood flow of the brain using single-photon emission computed tomography (SPECT) were obtained. The SPECT was analyzed semiquantitatively. Analysis of variance tests were conducted on total SPECT scores in each of the NDI groups (P < .05). Univariate correlations were obtained between blockage, pain, and SPECT scores, as well as age and duration. A multivariate analysis was then conducted., Results: Group 1 (mild) consisted of 14 patients. Cerebral perfusion measured by SPECT was normal in all 8 brain regions. Group 2 (moderate) consisted of 16 patients. In this group, a decrease in cerebral perfusion was observed (range, 20%-35%), predominantly in the parietal and frontal zones. Group 3 (severe) consisted of 15 patients. In this group, the decrease in cerebral perfusion observed was from 30% to 45%, again predominantly in the parietal and frontal zones. A significant difference was found between NDI groups ("moderate" and "severe" showed significantly greater hypoperfusion than "mild"). Total blockage score correlated with SPECT scores at r = 0.47, P = .001. In a multivariate analysis, NDI scores contributed 39% of the variance of SPECT scores., Conclusion: In this group of patients with neck and/or upper back pain, NDI scores strongly predicted cerebral hypoperfusion. Spinal joint dysfunction may be involved via hyperactivity in the regional sympathetic nervous system., (Copyright © 2012 National University of Health Sciences. Published by Mosby, Inc. All rights reserved.)

Objectives: The purpose of this study was to determine the role of standard and novel (cervical) nonorganic signs in patients with chronic whiplash-associated disorder (WAD)., Methods: Chronic WAD I to III patients (>3 months) were recruited from private chiropractic practice in Canada. Subjects completed a Neck Disability Index (NDI), Tampa Scale for Kinesiophobia (TSK), pain visual analog scale, and pain diagram. Clinical and demographic data were also obtained. Nine standard nonorganic pain behavior tests and 4 novel cervical nonorganic simulation signs (C-NOSS) tests were applied. Bivariate correlations were obtained with the Pearson correlation coefficient. Items achieving statistical significance on univariate analysis were loaded in a sequential linear regression analysis. Post hoc analyses were conducted with analysis of variance tests of NDI and TSK scores., Results: Ninety-one subjects were investigated (49 males and 42 females), with a mean age of 41.7 (SD, 14.7) years and a mean duration of 9.4 (SD, 11.2) months. Because mean NDI scores were 57.5 (SD, 17.8) and mean pain scores were 68.3 (SD, 21.0), this sample represents moderate-to-severe WAD. Fair to moderately strong correlations were obtained between the NDI and the TSK, pain visual analog scale and nonorganic symptoms and signs (NOS-9) and C-NOSS scores, but not with "age," "sex," or "duration." The NOS-9 and C-NOSS scores correlated most strongly at 0.70. A multivariate model accounting for 53% of the variance of the NDI scores (P < .001) was obtained with the TSK, pain severity, and NOS-9 scores. There was no significant correlation between C-NOSS and TSK scores. At least 25% of subjects scored either 5 of 9 or 2 of 4 on the NOS-9 and C-NOSS tests, respectively., Conclusions: Based on the findings of this study, nonorganic signs should be considered in the interpretation of self-rated disability in patients with moderate-to-severe chronic WAD., (Copyright © 2011 National University of Health Sciences. Published by Mosby, Inc. All rights reserved.)

The purpose of this study was to identify the characteristics of Olympic medal winners (gold, silver, bronze) who competed in the 2008 Beijing Olympic Games and compare these characteristics to those who competed but did not earn medals. We have also descriptively analysed the 2008 data in comparison to the 2004 data (Kazemi et al., 2009), and 2000 data (Kazemi et al., 2006) and summarized changes that were identified. This study as well as the last two studies did not find any statistically significant differences between winners and non-winners with regards to average age, weight, height and BMI. There are, however, some trends that were observed. Female winners were slightly younger, shorter, with greater BMI's versus non-winners. There was a significant decrease in frequency of warnings from 2004 to 2008. Unlike 2004, the 2008 Olympic Taekwondo competitors used more defensive kicks to score. These suggest a shift from aggressive tactics to score to a more conservative one.

Objective: To evaluate the impact of an exercise program organized into supervised walking groups in subjects with type 2 diabetes., Research Design and Methods: Fifty-nine diabetic subjects were randomized to a control group receiving standard lifestyle recommendations or an intervention group assigned to three supervised walking sessions per week and counseling. Changes in metabolic features, weight, 6-min walk test, prescription of antidiabetic medications, and overall physical activity were assessed., Results: Functional capacity and overall physical activity were higher in the intervention group, whereas metabolic changes were not different between groups after 4 months. However, in subjects who attended at least 50% of scheduled walking sessions, changes in A1C and fasting glucose were greater than in control subjects. Discontinuation or reduction of antidiabetic drugs occurred in 33% of these patients versus 5% of control subjects (P<0.05)., Conclusions: Supervised walking may be beneficial in diabetic subjects, but metabolic improvement requires adequate compliance.

We sought to determine if simulated malingering trials of isometric cervical muscular strength in flexion, extension and right/left bending are substantially different from maximum effort trials in young, healthy subjects. A convenience sample of healthy, young adult subjects was used (M=9, F=9) who were free of neck pain. A uniaxial load cell was used to measure forces (N) produced by three trials of isometric flexion, extension and bilateral bending contractions of the head/neck muscles in two modes: comfortable maximum (MAX) and simulated (insincere) malingering (INSIN). An ANOVA model was created and tested post-hoc for paired differences within and between modes and genders. A separate ANOVA was conducted to test for differences in the ratio between flexion and extension (F/E ratio). In MAX mode, males were stronger in all ranges vs females; the expected F/E and bilateral ratios were demonstrated and good consistency of effort within and between trials was demonstrated by low CV's and high ICC's, respectively. In INSIN mode, all mean peak values were significantly lower in both genders; however, the difference between genders disappeared. Within-trial consistency was much poorer with significantly higher CV's while between-trial variability was good as demonstrated by high ICC's. The flexion/extension ratio was increased in INSIN vs MAX, with no difference between genders. It appears that simulated malingering trials produced consistent patterns of deviation from maximal effort trials: reduced peak values, increased flexion/extension ratio and increased variability of within-trial effort. These findings may provide a basis for valid indicators of insincere effort in neck pain patients.

Objective: Sitting has been identified as a cause of mechanical low back pain. The purpose of this study was to use plain film x-rays to measure lumbar spine and pelvic posture differences between standing and sitting., Methods: Eight male subjects were radiographed standing and sitting in an automobile seat. Measures of lumbar lordosis, intervertebral disk angles, lumbosacral angle, lumbosacral lordosis, and sacral tilt were completed. One-way analysis of variance (alpha = .05) was conducted on the variables stated above. A Bland-Altman analysis was conducted to assess agreement and repeatability of the lumbar lordosis angle using 2 raters., Results: Lumbar lordosis values in standing (average, 63 degrees +/- 15 degrees ) and sacral inclination (average, 43 degrees +/- 10 degrees ) decreased by 43 degrees and 44 degrees , respectively, in sitting. Intervertebral joint angles in sitting underwent substantial flexion (L1/L2-5 degrees [+/-3 degrees ], L2/L3-7 degrees [+/-3 degrees ], L3/L4-8 degrees [+/-3 degrees ], L4/L5-13 degrees [+/-3 degrees ], and L5/S1-4 degrees [+/-10 degrees ]). Measures of lumbar lordosis; intervertebral disk angles between L2/L3, L3/L4, and L4/L5; lumbosacral lordosis; lumbosacral angle; and sacral tilt were significantly decreased between standing and sitting (P < .001). Intervertebral disk angle between L5/S1 was not significantly different. Analysis using the Bland-Altman technique found good agreement and stable repeatability of measures with no statistical significant differences between or within raters (R1, P = .8474; R2, P = .4402; and R-R2, P = .8691)., Conclusion: The significant differences in lumbar and pelvic measures from standing to sitting further emphasize the range of motion experienced at vertebral levels in sitting. Based on the results of this study, interventions to return motion segments to a less flexed posture should be investigated because they may play a role in preventing injury and low back pain., (Copyright 2010 National University of Health Sciences. Published by Mosby, Inc. All rights reserved.)