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A survey was conducted to identify demographics and standards of care for treatment of hypopharyngeal squamous cell carcinoma in the United States. Data were accrued from voluntary submission of cancer registry and medical chart information from 769 hospitals representing 2939 cases diagnosed from 1980 to 1985 and 1990 to 1992. Clinical findings, diagnostic procedures employed, treatment practices, and outcome are presented. Overall, 5-year disease-specific survival was 33.4%, which segregated to 63.1% (stage I), 57.5% (stage II), 41.8% (stage III), and 22% (stage IV). Survival was best for patients treated with surgery only (50.4%), similar with combined surgery and irradiation (48%), and worse with irradiation only (25.8%). This analysis provides a standard to which current treatment practice and future clinical trials may be compared. [ABSTRACT FROM AUTHOR]

Seasonally abundant arthropods are a crucial food source for many migratory birds that breed in the Arctic. In cold environments, the growth and emergence of arthropods are particularly tied to temperature. Thus, the phenology of arthropods is anticipated to undergo a rapid change in response to a warming climate, potentially leading to a trophic mismatch between migratory insectivorous birds and their prey. Using data from 19 sites spanning a wide temperature gradient from the Subarctic to the High Arctic, we investigated the effects of temperature on the phenology and biomass of arthropods available to shorebirds during their short breeding season at high latitudes. We hypothesized that prolonged exposure to warmer summer temperatures would generate earlier peaks in arthropod biomass, as well as higher peak and seasonal biomass. Across the temperature gradient encompassed by our study sites (>10°C in average summer temperatures), we found a 3-day shift in average peak date for every increment of 80 cumulative thawing degree-days. Interestingly, we found a linear relationship between temperature and arthropod biomass only below temperature thresholds. Higher temperatures were associated with higher peak and seasonal biomass below 106 and 177 cumulative thawing degree-days, respectively, between June 5 and July 15. Beyond these thresholds, no relationship was observed between temperature and arthropod biomass. Our results suggest that prolonged exposure to elevated temperatures can positively influence prey availability for some arctic birds. This positive effect could, in part, stem from changes in arthropod assemblages and may reduce the risk of trophic mismatch., (© 2024 His Majesty the King in Right of Canada and The Authors. Global Change Biology published by John Wiley & Sons Ltd. Reproduced with the permission of the Minister of Environment and Climate Change Canada. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Patients with metastatic acral lentiginous melanoma (ALM) suffer worse outcomes relative to patients with other forms of cutaneous melanoma (CM), and do not benefit as well to approved melanoma therapies. Identification of cyclin-dependent kinase 4 and 6 (CDK4/6) pathway gene alterations in >60% of ALMs has led to clinical trials of the CDK4/6 inhibitor (CDK4i/6i) palbociclib for ALM; however, median progression free survival with CDK4i/6i treatment was only 2.2 months, suggesting existence of resistance mechanisms. Therapy resistance in ALM remains poorly understood; here we report hyperactivation of MAPK signaling and elevated cyclin D1 expression serve as a mechanism of intrinsic early/adaptive CDK4i/6i resistance. ALM cells that have acquired CDK4i/6i resistance following chronic treatment exposure also exhibit hyperactivation of the MAPK pathway. MEK and/or ERK inhibition increases CDK4i/6i efficacy against therapy naïve and CDK4i/6i-resistant AM cells in xenograft and patient-derived xenograft (PDX) models and promotes a defective DNA repair, cell cycle arrested and apoptotic program. Notably, gene alterations poorly correlate with protein expression of cell cycle proteins in ALM or efficacy of CDK4i/6i, urging additional strategies when stratifying patients for CDK4i/6i trial inclusion. Concurrent targeting of the MAPK pathway and CDK4/6 represents a new approach for patients with metastatic ALM to improve outcomes., (© 2023. The Author(s).)

TidyGEO is a Web-based tool for downloading, tidying, and reformatting data series from Gene Expression Omnibus (GEO). As a freely accessible repository with data from over 6 million biological samples across more than 4000 organisms, GEO provides diverse opportunities for secondary research. Although scientists may find assay data relevant to a given research question, most analyses require sample-level annotations. In GEO, such annotations are stored alongside assay data in delimited, text-based files. However, the structure and semantics of the annotations vary widely from one series to another, and many annotations are not useful for analysis purposes. Thus, every GEO series must be tidied before it is analyzed. Manual approaches may be used, but these are error prone and take time away from other research tasks. Custom computer scripts can be written, but many scientists lack the computational expertise to create such scripts. To address these challenges, we created TidyGEO, which supports essential data-cleaning tasks for sample-level annotations, such as selecting informative columns, renaming columns, splitting or merging columns, standardizing data values, and filtering samples. Additionally, users can integrate annotations with assay data, restructure assay data, and generate code that enables others to reproduce these steps., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

Purpose: Patients who represent the negative biomarker population, those tested for a biomarker but found to be negative, are a critical component of the growing molecular data repository. Many next-generation sequencing (NGS)-based tumor sequencing panels test hundreds of genes, but most laboratories do not provide explicit negative results on test reports nor in their structured data. However, the need for a complete picture of the testing landscape is significant. Syapse has created an internal ingestion and data transformation pipeline that uses the power of natural language processing (NLP), terminology management, and internal rulesets to semantically align data and infer negative results not explicitly stated., Patients and Methods: Patients within the learning health network with a cancer diagnosis and at least one NGS-based molecular report were included. To obtain this critical negative result data, laboratory gene panel information was extracted and transformed using NLP techniques into a semistructured format for analysis. A normalization ontology was created in tandem. With this approach, we were able to successfully leverage positive biomarker data to derive negative data and create a comprehensive data set for molecular testing paradigms., Results: The application of this process resulted in a drastic improvement in data completeness and clarity, especially when compared with other similar data sets., Conclusion: The ability to accurately determine positivity and testing rates among patient populations is imperative. With only positive results, it is impossible to draw conclusions about the entire tested population or the characteristics of the subgroup who are negative for the biomarker in question. We leverage these values to perform quality checks on ingested data, and end users can easily monitor their adherence to testing recommendations.

Background: The United States continues to be plagued with pervasive health disparities. Leading health and professional organizations acknowledge structural racism as a contributing factor for the lack of a racially diverse nursing workforce particularly those serving in leadership roles which could help to mitigate health disparities among historically stigmatized populations., Purpose: Purpose Lack of funding for Historically Black Colleges and Universities (HBCUs) and lack of meaningful partnerships, stymie efforts that can be made by nursing programs at HBCUs., Discussion: Discussion This position paper examines collaborative actions that can address upstream factors that perpetuate healthcare disparities through deep engagement between the policymakers, professional associations, industry, and educational institutions., Methods: Faculty representing HBCU's and predominately White institutions, professional organizations, and staff met via videoconference to refine the focus of the paper, determine topic areas for writing teams, and refine details which occurred during weekly meetings., Conclusion: To disengage from structural racism, three critical recommendations are amplified with associated examples., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Lysosomal autophagy inhibition (LAI) with hydroxychloroquine or DC661 can enhance cancer therapy, but tumor regrowth is common. To elucidate LAI resistance, proteomics and immunoblotting demonstrated that LAI induced lipid metabolism enzymes in multiple cancer cell lines. Lipidomics showed that LAI increased cholesterol, sphingolipids, and glycosphingolipids. These changes were associated with striking levels of GM1+ membrane microdomains (GMM) in plasma membranes and lysosomes. Inhibition of cholesterol/sphingolipid metabolism proteins enhanced LAI cytotoxicity. Targeting UDP-glucose ceramide glucosyltransferase (UGCG) synergistically augmented LAI cytotoxicity. Although UGCG inhibition decreased LAI-induced GMM and augmented cell death, UGCG overexpression led to LAI resistance. Melanoma patients with high UGCG expression had significantly shorter disease-specific survival. The FDA-approved UGCG inhibitor eliglustat combined with LAI significantly inhibited tumor growth and improved survival in syngeneic tumors and a therapy-resistant patient-derived xenograft. These findings nominate UGCG as a new cancer target, and clinical trials testing UGCG inhibition in combination with LAI are warranted., Significance: We discovered UGCG-dependent lipid remodeling drives resistance to LAI. Targeting UGCG with a drug approved for a lysosomal storage disorder enhanced LAI antitumor activity without toxicity. LAI and UGCG inhibition could be tested clinically in multiple cancers. This article is highlighted in the In This Issue feature, p. 247., (©2022 American Association for Cancer Research.)

Methamphetamine (MA) is a highly addictive stimulant with recent upward trends in prevalence and associated public health problems. Drug demand, as assessed by hypothetical purchasing tasks, has been useful in addictions research and may help our understanding of the factors influencing MA use. However, no studies have assessed MA demand using current models of demand. The purpose of the current study was to assess demand for MA using a hypothetical drug purchasing task. Given high rates of cigarette smoking among MA users, it was of interest also to assess and compare demand for MA relative to cigarettes. Participants consisted of non-treatment-seeking volunteers with MA use disorder (N = 18), of whom 17 reported daily smoking. Results showed the exponentiated demand model provided a good fit to consumption data. Results from Bayesian generalized linear modeling demonstrated multiple positive relationships (posterior probability ≥75%) between self-reported drug use (days MA used in the past 30 days, cigarettes smoked per day) and indices of demand for each drug (Qo, Omax, Pmax, and break point). Comparing MA to cigarettes, results from Bayesian generalized linear mixed modeling revealed greater abuse liability for MA compared to cigarettes (posterior probability ≥99%) based on α and essential value. Overall, the findings of the current study support the feasibility and validity of the exponentiated demand model for assessing demand for drugs among individuals with MA use disorder. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Diabetes is a metabolic syndrome rooted in impaired insulin and/or glucagon secretory responses within the pancreatic islets of Langerhans (islets). Insulin secretion is primarily regulated by two key factors: glucose-mediated ATP production and G-protein coupled receptors (GPCRs) signaling. GPCR kinase 2 (GRK2), a key regulator of GPCRs, is reported to be downregulated in the pancreas of spontaneously obesogenic and diabetogenic mice (ob/ob). Moreover, recent studies have shown that GRK2 non-canonically localizes to the cardiac mitochondrion, where it can contribute to glucose metabolism. Thus, islet GRK2 may impact insulin secretion through either mechanism. Utilizing Min6 cells, a pancreatic ß-cell model, we knocked down GRK2 and measured glucose-mediated intracellular calcium responses and insulin secretion. Silencing of GRK2 attenuated calcium responses, which were rescued by pertussis toxin pre-treatment, suggesting a Gαi/o-dependent mechanism. Pancreatic deletion of GRK2 in mice resulted in glucose intolerance with diminished insulin secretion. These differences were due to diminished insulin release rather than decreased insulin content or gross differences in islet architecture. Furthermore, a high fat diet feeding regimen exacerbated the metabolic phenotype in this model. These results suggest a new role for pancreatic islet GRK2 in glucose-mediated insulin responses that is relevant to type 2 diabetes disease progression.

Background: Optimal management of severe and complex injuries to the medial knee ligaments remains uncertain. This systematic review evaluates outcomes from randomised controlled trials investigating interventions for treating injuries of medial ligaments of the knee., Methods: Randomised controlled clinical trials evaluating interventions for treating injuries of the medial knee ligaments were identified through searching EMBASE, Medline, Cochrane, WHO, and clinicaltrials.org. Comparisons were made between different non-operative interventions, surgical versus non-operative interventions, different surgical interventions, and different postoperative interventions. Primary outcome measures included patient reported outcome measures (PROM) of knee function, pain, and treatment failure., Results: 412 trial records were identified; 259 were non-redundant and distinct studies, of which eight were included for analysis. No differences between operative and non-operative management strategies were found for either primary outcome: Lysholm and IKDC scores. Compared to non-operative interventions, operative interventions resulted in reduced quadriceps strength at eight weeks (mean difference (MD) 29 (% knee extension strength deficit compared with unaffected knee); 95%CI 3.89-54.11) and were associated with greater incidence of minor complications (relative risk (RR) 25; 95%CI: 1.51-421, and RR 25; 95%CI: 1.50-416.58, respectively). Quadriceps strength between 16 and 52 weeks was similar in non-operative and operative groups (MD 20; 95%CI -1.92-41.92). Functional rehabilitation was associated with reduced valgus laxity at six weeks compared to bracing ((MD) -1.40; 95%CI: -2.21-0.59)., Conclusions: Non-operative interventions provided similar functional results to operative interventions for grade I-III injuries of the medial collateral ligaments. Non-operative intervention was associated with improved quadriceps strength during rehabilitation, and fewer complications, compared to operative interventions., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

Cantu syndrome (CS) is caused by gain-of-function (GOF) mutations in pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) channel subunits, the most common mutations being SUR2[R1154Q] and SUR2[R1154W], carried by approximately 30% of patients. We used CRISPR/Cas9 genome engineering to introduce the equivalent of the human SUR2[R1154Q] mutation into the mouse ABCC9 gene. Along with minimal CS disease features, R1154Q cardiomyocytes and vascular smooth muscle showed much lower KATP current density and pinacidil activation than WT cells. Almost complete loss of SUR2-dependent protein and KATP in homozygous R1154Q ventricles revealed underlying diazoxide-sensitive SUR1-dependent KATP channel activity. Surprisingly, sequencing of SUR2 cDNA revealed 2 distinct transcripts, one encoding full-length SUR2 protein; and the other with an in-frame deletion of 93 bases (corresponding to 31 amino acids encoded by exon 28) that was present in approximately 40% and approximately 90% of transcripts from hetero- and homozygous R1154Q tissues, respectively. Recombinant expression of SUR2A protein lacking exon 28 resulted in nonfunctional channels. CS tissue from SUR2[R1154Q] mice and human induced pluripotent stem cell-derived (hiPSC-derived) cardiomyocytes showed only full-length SUR2 transcripts, although further studies will be required in order to fully test whether SUR2[R1154Q] or other CS mutations might result in aberrant splicing and variable expressivity of disease features in human CS.

Kubelka et al (Reports, 9 November 2018, p. 680) claim that climate change has disrupted patterns of nest predation in shorebirds. They report that predation rates have increased since the 1950s, especially in the Arctic. We describe methodological problems with their analyses and argue that there is no solid statistical support for their claims., (Copyright © 2019, American Association for the Advancement of Science.)

Cantu syndrome (CS) is characterized by multiple vascular and cardiac abnormalities including vascular dilation and tortuosity, systemic hypotension, and cardiomegaly. The disorder is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) channel subunits. However, there is little understanding of the link between molecular dysfunction and the complex pathophysiology observed, and there is no known treatment, in large part due to the lack of appropriate preclinical disease models in which to test therapies. Notably, expression of Kir6.1 and SUR2 does not fully overlap, and the relative contribution of KATP GOF in various cardiovascular tissues remains to be elucidated. To investigate pathophysiologic mechanisms in CS we have used CRISPR/Cas9 engineering to introduce CS-associated SUR2[A478V] and Kir6.1[V65M] mutations to the equivalent endogenous loci in mice. Mirroring human CS, both of these animals exhibit low systemic blood pressure and dilated, compliant blood vessels, as well dramatic cardiac enlargement, the effects being more severe in V65M animals than in A478V animals. In both animals, whole-cell patch-clamp recordings reveal enhanced basal KATP conductance in vascular smooth muscle, explaining vasodilation and lower blood pressure, and demonstrating a cardinal role for smooth muscle KATP dysfunction in CS etiology. Echocardiography confirms in situ cardiac enlargement and increased cardiac output in both animals. Patch-clamp recordings reveal reduced ATP sensitivity of ventricular myocyte KATP channels in A478V, but normal ATP sensitivity in V65M, suggesting that cardiac remodeling occurs secondary to KATP overactivity outside of the heart. These SUR2[A478V] and Kir6.1[V65M] animals thus reiterate the key cardiovascular features seen in human CS. They establish the molecular basis of the pathophysiological consequences of reduced smooth muscle excitability resulting from SUR2/Kir6.1-dependent KATP GOF, and provide a validated animal model in which to examine potential therapeutic approaches to treating CS.

Background and Objectives: Delay discounting is associated with numerous clinically significant aspects of substance use disorders (SUDs). Recent studies have demonstrated that different models for assessing discounting may result in disparate conclusions. The current study compared two discounting tasks: money now versus money later (M-M) and methamphetamine now versus money later (MA-M) among non-treatment seeking individuals (N = 59) with methamphetamine use disorder (MAUD). Results from each task were assessed using three different models for assessing delay discounting., Methods: Discounting data were fit to three models of discounting, log k using Mazur's hyperbolic formula, area under the curve (AUC), and an alternative AUC model in which the delay values have been log transformed (AUClog)., Results: For both discounting tasks, the distribution of model-related outcomes were normally distributed when using log k and AUClog, but skewed for AUC. Discounting in the MA-M task was significantly greater compared to the M-M task when using log k and AUClog but not AUC., Conclusion: To our knowledge, the current study is the first to report significantly greater discounting in a MA-M relative to M-M discounting task among individuals with MAUD, an outcome consistent with other psychomotor stimulants and drugs of abuse., Scientific Significance: The differential results observed across the three discounting models reaffirm potential issues with AUC noted in recent studies and highlight that researchers must be cautious when deciding on their final model of discounting. (Am J Addict 2018;XX:1-8)., (© 2018 American Academy of Addiction Psychiatry.)

The ideal free distribution assumes that animals select habitats that are beneficial to their fitness. When the needs of dependent offspring differ from those of the parent, ideal habitat selection patterns could vary with the presence or absence of offspring. We test whether habitat selection depends on reproductive state due to top-down or bottom-up influences on the fitness of woodland caribou ( Rangifer tarandus caribou ), a threatened, wide-ranging herbivore. We combined established methods of fitting resource and step selection functions derived from locations of collared animals in Ontario with newer techniques, including identifying calf status from video collar footage and seasonal habitat selection analysis through latent selection difference functions. We found that females with calves avoided predation risk and proximity to roads more strongly than females without calves within their seasonal ranges. At the local scale, females with calves avoided predation more strongly than females without calves. Females with calves increased predation avoidance but not selection for food availability upon calving, whereas females without calves increased selection for food availability across the same season. These behavioral responses suggest that habitat selection by woodland caribou is influenced by reproductive state, such that females with calves at heel use habitat selection to offset the increased vulnerability of their offspring to predation risk.

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.

Delay discounting describes how a reward loses value as a function of increasing delay to its receipt and has been reliably associated with a variety of vulnerable populations including those with substance use disorders (SUDs). Two commonly used models to assess delay discounting in the field of SUDs include log k derived from Mazur's hyperbolic equation and area under the curve (AUC). In the current study, we compared log k with AUC on delay discounting data obtained from non-treatment seeking, cocaine- and methamphetamine-dependent volunteers. We specifically chose this population in order to obtain a distribution of relatively steep discounters. The results show that the relationship between AUC and log k is better described by a quadratic rather than a linear function. In other words, changes in discounting, as measured by AUC and log k , are reflected differently across a range of obtained responses. Additionally, the distribution of AUC values was skewed, which appears to be more likely among populations exhibiting greater discounting. Finally, closer examination of indifference points revealed that AUC was almost perfectly predicted by the area from the two longest delays, with relatively less input from shorter delays. Given these results, researchers should exercise additional caution when deciding which method to assess discounting data and how final results are to be interpreted, particularly when dealing with relatively high rates of discounting. High rates of discounting are likely in populations with impulsive disorders such as those with SUDs.

Loss or alteration of forest ecosystems due to anthropogenic activities has prompted the need for mitigation measures aimed at protecting habitat for forest-dependent wildlife. Understanding how wildlife respond to such management efforts is essential for achieving conservation targets. Boreal caribou are a species of conservation concern due to the impacts of human induced habitat alteration; however the effects of habitat management activities are poorly understood. We assessed the relationship between large scale patterns in forest harvesting and caribou spatial behaviours over a 20-year period, spanning a change in forest management intended to protect caribou habitat. Caribou range size, fidelity, and proximity to forest harvests were assessed in relation to change in harvest patterns through time and across two landscapes that varied widely in natural disturbance and community dynamics. We observed up to 89% declines in total area harvested within our study areas, with declining harvest size and aggregation. These landscape outcomes were coincident with caribou exhibiting greater fidelity and spacing farther away from disturbances at smaller scales, hypothesized to be beneficial for acquiring food and avoiding predators. Contrary to our expectation that the large scale maintenance of habitat patches would permit caribou to space away from disturbance, their proximity to harvest blocks at the population range scale did not decrease through time, suggesting that movement toward landscape recovery for caribou in previously harvested regions will likely stretch over multiple decades. Caribou spatial behaviours varied across the two landscapes independently of forest management. Our study underlines the importance of understanding both changes in industry demands, as well as natural landscape variation in habitat when managing wildlife.

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., Competing Interests: R.T.B., M.L.T., A.M., L.C.P. and S.K.P. are current or past employees of and G.P.Y. is a consultant for Clinical Genomics Pty Ltd. The work described was planned and conducted jointly by employees of Clinical Genomics Pty Ltd. and of CSIRO.

Parasites are considered to be an important selective force in host evolution but ecological studies of host-parasite systems are usually short-term providing only snap-shots of what may be dynamic systems. We have conducted four surveys of helminths of bank voles at three ecologically similar woodland sites in NE Poland, spaced over a period of 11 years, to assess the relative importance of temporal and spatial effects on helminth infracommunities. Some measures of infracommunity structure maintained relative stability: the rank order of prevalence and abundance of Heligmosomum mixtum, Heligmosomoides glareoli and Mastophorus muris changed little between the four surveys. Other measures changed markedly: dynamic changes were evident in Syphacia petrusewiczi which declined to local extinction, while the capillariid Aonchotheca annulosa first appeared in 2002 and then increased in prevalence and abundance over the remaining three surveys. Some species are therefore dynamic and both introductions and extinctions can be expected in ecological time. At higher taxonomic levels and for derived measures, year and host-age effects and their interactions with site are important. Our surveys emphasize that the site of capture is the major determinant of the species contributing to helminth community structure, providing some predictability in these systems.

The authors describe a collaborative outcomes resource network (ACORN) and the suite of measurement and decision support tools (ACORN Toolkit) that have emerged from this collaboration for the purpose of providing clinical feedback to therapists. The ACORN Toolkit is most accurately described as a comprehensive clinical information system designed to increase the value of mental health services across large systems of care. It was built to integrate large datasets from multiple sources including outcome data, client demographics and diagnostic data, therapist credentialing information, pharmacy data, and service claims data. For the limited purposes of this article, the authors focus on the ACORN Toolkit for measuring and how it has contributed to improving outcomes in psychotherapy. Implications to current practice and future training are provided., ((c) 2015 APA, all rights reserved).)

A number of studies have established that transcranial direct current stimulation (tDCS) modulates cortical excitability. We previously demonstrated polarity dependent changes in parietal lobe blood oxygen level dependent (BOLD) fMRI in a group of young adults during a spatial navigation task [15]. Here we used resting state functional connectivity (rsFC) to examine whether analogous changes were also evident during the resting state. Participants were randomized to either a parietal-anodal, frontal-cathodal (P+F-) or the opposite montage (P-F+) and received 20min of tDCS (2mA) before undergoing resting-state fMRI. rsFC was evaluated between the groups by placing a seed in the medial superior parietal lobule (mSPL), which was under the target electrode. rsFC between the mSPL and a number of other areas involved in spatial navigation, scene processing, and sensorimotor processing was significantly higher in the P+F- than the P-F+ group. Thus, the modulatory effects of tDCS were evident during rest and suggest that stimulation primes not just the underlying neocortex but an extended network that can be recruited as necessary during active task performance., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

1. Although local variation in territorial predator density is often correlated with habitat quality, the causal mechanism underlying this frequently observed association is poorly understood and could stem from facultative adjustment in either group size or territory size. 2. To test between these alternative hypotheses, we used a novel statistical framework to construct a winter population-level utilization distribution for wolves (Canis lupus) in northern Ontario, which we then linked to a suite of environmental variables to determine factors influencing wolf space use. Next, we compared habitat quality metrics emerging from this analysis as well as an independent measure of prey abundance, with pack size and territory size to investigate which hypothesis was most supported by the data. 3. We show that wolf space use patterns were concentrated near deciduous, mixed deciduous/coniferous and disturbed forest stands favoured by moose (Alces alces), the predominant prey species in the diet of wolves in northern Ontario, and in proximity to linear corridors, including shorelines and road networks remaining from commercial forestry activities. 4. We then demonstrate that landscape metrics of wolf habitat quality - projected wolf use, probability of moose occupancy and proportion of preferred land cover classes - were inversely related to territory size but unrelated to pack size. 5. These results suggest that wolves in boreal ecosystems alter territory size, but not pack size, in response to local variation in habitat quality. This could be an adaptive strategy to balance trade-offs between territorial defence costs and energetic gains due to resource acquisition. That pack size was not responsive to habitat quality suggests that variation in group size is influenced by other factors such as intraspecific competition between wolf packs., (© 2015 The Authors. Journal of Animal Ecology © 2015 British Ecological Society.)

Movement patterns offer a rich source of information on animal behaviour and the ecological significance of landscape attributes. This is especially useful for species occupying remote landscapes where direct behavioural observations are limited. In this study, we fit a mechanistic model of animal cognition and movement to GPS positional data of woodland caribou (Rangifer tarandus caribou; Gmelin 1788) collected over a wide range of ecological conditions. The model explicitly tracks individual animal informational state over space and time, with resulting parameter estimates that have direct cognitive and ecological meaning. Three biotic landscape attributes were hypothesized to motivate caribou movement: forage abundance (dietary digestible biomass), wolf (Canis lupus; Linnaeus, 1758) density and moose (Alces alces; Linnaeus, 1758) habitat. Wolves are the main predator of caribou in this system and moose are their primary prey. Resulting parameter estimates clearly indicated that forage abundance is an important driver of caribou movement patterns, with predator and moose avoidance often having a strong effect, but not for all individuals. From the cognitive perspective, our results support the notion that caribou rely on limited sensory inputs from their surroundings, as well as on long-term spatial memory, to make informed movement decisions. Our study demonstrates how sensory, memory and motion capacities may interact with ecological fitness covariates to influence movement decisions by free-ranging animals., (© 2015 The Authors. Journal of Animal Ecology © 2015 British Ecological Society.)

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 β 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.

Energetic balance is a central driver of individual survival and population change, yet estimating energetic costs in free- and wide-ranging animals presents a significant challenge. Animal-borne activity monitors (using accelerometer technology) present a promising method of meeting this challenge and open new avenues for exploring energetics in natural settings. To determine the behaviours and estimated energetic costs associated with a given activity level, three captive reindeer (Rangifer tarandus tarandus) at the Toronto Zoo were fitted with collars and observed for 53 h. Activity patterns were then measured over 13 months for 131 free-ranging woodland caribou (R. t. caribou) spanning 450,000 km(2) in northern Ontario. The captive study revealed a positive but decelerating relationship between activity level and energetic costs inferred from previous behavioural studies. Field-based measures of activity were modelled against individual displacement, vegetation abundance (Normalized Difference Vegetation Index), snow depth and temperature, and the best fit model included all parameters and explained over half of the variation in the data. Individual displacement was positively related to activity levels, suggesting that broad differences in energetic demands are influenced by variation in movement rates. After accounting for displacement, activity was highest at intermediate levels of vegetation abundance, presumably due to foraging behaviour. Snow depth, probably associated with digging for winter forage, moderately increased activity. Activity levels increased significantly at the coldest winter temperatures, suggesting the use of behavioural thermoregulation by caribou. These interpretations of proximate causal factors should be regarded as hypotheses subject to validation under normal field conditions. These results illustrate the landscape characteristics that increase energetic demands for caribou and confirm the great potential for the use of accelerometry in studies of animal energetics., (© 2014 The Authors. Journal of Animal Ecology © 2014 British Ecological Society.)

Background: Allocentric navigation declines with age and neurologic disease whereas egocentric navigation does not; differences that likely arise from maladaptive changes in brain regions mediating spatial (parietal cortex; hippocampus) but not procedural processing (caudate nucleus). Transcranial direct current stimulation (tDCS) holds promise for treating such decline given its ability to modulate neuronal excitability, but its effects have yet to be examined on spatial navigation., Objectives/hypotheses: Using healthy young adults as a model, Study 1 intended to validate a novel spatial navigation paradigm using functional magnetic resonance imaging (fMRI). Using these data to determine targets for tDCS, Study 2 aimed to determine if 1) stimulation modulates activation in a polarity-specific manner; 2) stimulation results in global and/or task-specific activation changes; 3) activation changes are accompanied by changes in effective connectivity., Methods: All participants underwent fMRI while learning allocentric and egocentric environments. Twelve participants completed Study 1. In Study 2, 16 participants were randomized to 20 min of tDCS (2 mA) using a montage with the anode over PZ and cathode over AF4 (P+F-) or the reverse montage (P-F+)., Results: Study 1 revealed that distinct networks preferentially mediate allocentric and egocentric navigation. Study 2 revealed polarity-dependent changes in activation and connectivity. The P+F- montage increased these measures in spatial regions, especially during allocentric navigation, and the caudate nucleus. Conversely, the P-F+ montage increased activation and connectivity in lateral prefrontal cortices and posterior hippocampus., Conclusions: These findings support the neuromodulatory effects of tDCS in non-motor areas and demonstrate proof-of-principle for ameliorating age- and disease-related decline in navigational abilities., (Published by Elsevier Inc.)

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.

Acute intermittent porphyria (AIP) is an autosomal dominant genetic defect in heme synthesis. Patients with this illness can have episodic life-threatening attacks characterized by abdominal pain, neurological deficits, and psychiatric symptoms. Feigning this illness has not been reported in the English language literature to date. Here, we report on a patient who presented to the hospital with an acute attack of porphyria requesting opiates. Diligent assessment of extensive prior treatment records revealed thirteen negative tests for AIP.

Advances in structural and functional neuroimaging techniques have unquestionably improved understanding of the development and progression of Alzheimer disease (AD), with evidence supporting regional (and network) change that underlies cognitive decline across the "healthy" aging/mild cognitive impairment (MCI)/AD spectrum. This review focuses on visual rating scales and volumetric analyses that could be easily integrated into clinical practice, followed by a review of functional neuroimaging findings suggesting that widespread cerebral dysfunction underlies the learning and memory deficits in MCI. Evidence of preserved neuroplasticity in this population and that cognitive rehabilitation techniques may capitalize on this plasticity to improve cognition in those with MCI is also discussed., (Published by Elsevier Inc.)

Some introduced populations thrive and evolve despite the presumed loss of diversity at introduction. We aimed to quantify the amount of genetic diversity retained at introduction in species that have shown evidence of adaptation to their introduced environments. Samples were taken from native and introduced ranges of Arctotheca populifolia and Petrorhagia nanteuilii. Using microsatellite data, we identified the source for each introduction, estimated genetic diversity in native and introduced populations, and calculated the amount of diversity retained in introduced populations. These values were compared to those from a literature review of diversity in native, confamilial populations and to estimates of genetic diversity retained at introduction. Gene diversity in the native range of both species was significantly lower than for confamilials. We found that, on average, introduced populations showing evidence of adaptation to their new environments retained 81% of the genetic diversity from the native range. Introduced populations of P. nanteuilii had higher genetic diversity than found in the native source populations, whereas introduced populations of A. populifolia retained only 14% of its native diversity in one introduction and 1% in another. Our literature review has shown that most introductions demonstrating adaptive ability have lost diversity upon introduction. The two species studied here had exceptionally low native range genetic diversity. Further, the two introductions of A. populifolia represent the largest percentage loss of genetic diversity in a species showing evidence of substantial morphological change in the introduced range. While high genetic diversity may increase the likelihood of invasion success, the species examined here adapted to their new environments with very little neutral genetic diversity. This finding suggests that even introductions founded by small numbers of individuals have the potential to become invasive.

Within the rapidly developing field of movement ecology, much attention has been given to studying the movement of individuals within a subset of their population's occupied range. Our understanding of the effects of landscape heterogeneity on animal movement is still fairly limited as it requires studying the movement of multiple individuals across a variety of environmental conditions. Gaining deeper understanding of the environmental drivers of movement is a crucial component of predictive models of population spread and habitat selection and may help inform management and conservation. In Ontario, woodland caribou (Rangifer tarandus caribou) occur along a wide geographical gradient ranging from the boreal forest to the Hudson Bay floodplains. We used high-resolution GPS data, collected from 114 individuals across a 450000 km(2) area in northern Ontario, to link movement behaviour to underlying local environmental variables associated with habitat permeability, predation risk and forage availability. We show that a great deal of observed variability in movement patterns across space and time can be attributed to local environmental conditions, with residual individual differences that may reflect spatial population structure. We discuss our results in the context of current knowledge of movement and caribou ecology and highlight potential applications of our approach to the study of wide-ranging animals., (© 2012 The Authors. Journal of Animal Ecology © 2012 British Ecological Society.)

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.

1. Better understanding of the mechanisms affecting demographic variation in ungulate populations is needed to support sustainable management of harvested populations. While studies of moose Alces alces L. populations have previously explored temporal variation in demographic processes, managers responsible for populations that span large heterogeneous landscapes would benefit from an understanding of how demography varies across biogeographical gradients in climate and other population drivers. Evidence of thresholds in population response to manageable and un-manageable drivers could aid resource managers in identifying limits to the magnitude of sustainable change. 2. Generalized additive models (GAMs) were used to evaluate the relative importance of population density, habitat abundance, summer and winter climatic conditions, primary production, and harvest intensity in explaining spatial variation in moose vital rates in Ontario, Canada. Tree regression was used to test for thresholds in the magnitudes of environmental predictor variables that significantly affected population vital rates. 3. Moose population growth rate was negatively related to moose density and positively related to the abundance of mixed deciduous habitat abundant in forage. Calf recruitment was negatively related to a later start of the growing season and calf harvest. The ratio of bulls to cows was related to male harvest and hunter access, and thresholds were evident in predictor variables for all vital rate models. 4. Findings indicate that the contributions of density-dependent and independent factors can vary depending on the scale of population process. The importance of density dependence and habitat supply to low-density ungulate populations was evident, and management strategies for ungulates may be improved by explicitly linking forest management and harvest. Findings emphasize the importance of considering summer climatic influences to ungulate populations, as recruitment in moose was more sensitive to the timing of vegetation green-up than winter severity. The efficacy of management decisions for harvested ungulates may require regional shifts in targets where populations span bioclimatic gradients. The use of GAMs in combination with recursive partitioning was demonstrated to be an informative analytical framework that captured nonlinear relationships common in natural processes and thresholds that are relevant to population management in diverse systems., (© 2011 The Author. Journal of Animal Ecology © 2011 British Ecological Society.)

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.

An uncharacterized gene locus (Chr16:hCG&#95;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.

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.

Brown and White (2009) proposed measures of discriminability and bias that accommodate additional dimensions of choice--and hence, bias--in conditional discriminations such as matching-to-sample and the yes-no signal detection task. Their proposed measures increase the statistical independence of discriminability and bias estimates, thus improving their accuracy. Because Brown and White's (2009) equations partition response data more than do standard equations, however, their measures have a slightly lower ceiling. Consequently, measurements can be less accurate when there are few trials and discriminability and bias are extreme. We introduce a computational estimation technique that overcomes this limitation. It estimates Brown and White's (2009) discriminability and bias measurements from an array of related measures that have a higher ceiling. Simulations show that resulting estimates of discriminability and bias are either comparable to or more accurate than measurements calculated from traditional equations or Brown and White's (2009) direct measures, even with few trials. A worked example of our technique may be downloaded from brm.psychonomic-journals.org/content/supplemental.

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., (Copyright (c) 2009 APA, all rights reserved.)