Assessing Dietary Outcomes in Intervention Studies: Pitfalls, Strategies, and Research Needs.

To inform strategies to improve the dietary intakes of populations, robust evaluations of interventions are required. This paper is drawn from a workshop held at the International Society of Behavioral Nutrition and Physical Activity 2017 Annual Meeting, and highlights considerations and research priorities relevant to measuring dietary outcomes within intervention studies. Self-reported dietary data are typically relied upon in such studies, and it is recognized that these data are affected by random and systematic error. Additionally, differential error between intervention and comparison groups or pre- and post-intervention can be elicited by the intervention itself, for example, by creating greater awareness of eating or drinking occasions or the desire to appear compliant. Differential reporting can render the results of trials incorrect or inconclusive by leading to biased estimates and reduced statistical power. The development of strategies to address intervention-related biases requires developing a better understanding of the situations and population groups in which interventions are likely to elicit differential reporting and the extent of the bias. Also needed are efforts to expand the feasibility and applications of biomarkers to address intervention-related biases. In the meantime, researchers are encouraged to consider the potential for differential biases in dietary reporting in a given study, to choose tools carefully and take steps to minimize and/or measure factors such as social desirability biases that might contribute to differential reporting, and to consider the implications of differential reporting for study results

Differential regulation of TROP2 release by PKC isoforms through vesicles and ADAM17

TROP2, a cancer cell surface protein with both pro-oncogenic and anti-oncogenic properties is cleaved by ADAM17. ADAM17 dependent cleavage requires novel PKC activity which is blocked by the ADAM10/ADAM17 inhibitor GW64 as well as by the PKC inhibitor Bim-1. Full length TROP2 release is induced by classical PKC activation and blocked by Gö6979, without affecting ADAM17 dependent TROP2 cleavage. Full length TROP2 is released in ectosomes, as inhibition of endocytosis did not prevent release. Inhibition of the atypical PKC isoform PKCζ stimulated metalloproteinase dependent N-terminal alternative TROP2 cleavage. The resulting alternative TROP2 cleavage product remains membrane associated via a disulphide bond, but is released in microvesicles with an average size of 107 nm. Inhibition of endocytosis following PKCζ inhibition prevented alternative cleavage and release of TROP2, suggesting that these events require endocytic uptake and exosomal release of the corresponding microvesicles. The alternative TROP2 cleavage product was also found in PC3 cell lysates following deglycosylation, and may represent a novel biomarker in prostate cancer

HIV Drug Resistance Surveillance Among Jamaican Men Who Have Sex with Men Should Be Prioritized for Reducing HIV Transmission

The prevalence of human immunodeficiency virus type 1 (HIV-1) is highest among men who have sex with men (MSM) in Jamaica but no genotypic data are available on the virus strains that are responsible for the epidemic among this key population. HIV-1 polymerase (pol) genes from 65 MSM were sequenced and used to predict drug resistance mutations. An HIV drug resistance prevalence of 28% (minimum 13%) was observed among this cohort, with the most frequent mutations conferring resistance to efavirenz, nevirapine, and lamivudine. Phylogenetic analysis of the sequences revealed 10 times the number of linked HIV infections among this cohort than respondent reporting. HIV treatment and prevention efforts in Jamaica could benefit significantly from Pol genotyping of the HIV strains infecting socially vulnerable MSM prior to initiating antiretroviral therapy (ART), as this would guide suppressive ART and unearth HIV transmission clusters to enable more effective delivery of treatment and prevention programs

Phase-Field Model of Mode III Dynamic Fracture

We introduce a phenomenological continuum model for mode III dynamic fracture that is based on the phase-field methodology used extensively to model interfacial pattern formation. We couple a scalar field, which distinguishes between ``broken'' and ``unbroken'' states of the system, to the displacement field in a way that consistently includes both macroscopic elasticity and a simple rotationally invariant short scale description of breaking. We report two-dimensional simulations that yield steady-state crack motion in a strip geometry above the Griffith threshold.Comment: submitted to PR

Tradition meets technology : building caring community online

Community has historically provided an essential psycho-spiritual framework for nursing. Changes in communication technology pose challenges for nurses internationally who create communities across borders. This article discusses The Bamboo Bridge online community, a project responding to the global call for nursing education about the complementarity of nursing and healing traditions. The project explores how technologies such as Centra and Ning promote community building and encourage belonging in members from 5 continents and 10 countries. This article includes detailed accounts of the project design, examples of cultural diplomacy as the emerging theoretical framework, and an African member’s perspective of online community.http://journals.lww.com/advancesinnursingscience/pages/default.aspxhb201

Regulation of the Distribution and Function of [ 125 I]Epibatidine Binding Sites by Chronic Nicotine in Mouse Embryonic Neuronal Cultures

ABSTRACT Chronic nicotine produces up-regulation of ␣4␤2* nicotinic acetylcholine receptors (nAChRs) (* denotes that an additional subunit may be part of the receptor). However, the extent of up-regulation to persistent ligand exposure varies across brain regions. The aim of this work was to study the cellular distribution and function of nAChRs after chronic nicotine treatment in primary cultures of mouse brain neurons. Initially, high-affinity [ 125 I]epibatidine binding to cell membrane homogenates from primary neuronal cultures obtained from diencephalon and hippocampus of C57BL/6J mouse embryos (embryonic days 16 -18) was measured. An increase in ␣4␤2*-nAChR binding sites was observed in hippocampus, but not in diencephalon, after 24 h of treatment with 1 M nicotine. However, a nicotine dose-dependent up-regulation of approximately 3.5-and 0.4-fold in hippocampus and diencephalon, respectively, was found after 96 h of nicotine treatment. A significant fraction of total [ 125 I]epibatidine binding sites in both hippocampus (45%) and diencephalon (65%) was located on the cell surface. Chronic nicotine (96 h) up-regulated both intracellular and surface binding in both brain regions without changing the proportion of those binding sites compared with control neurons. The increase in surface binding was not accompanied by an increase in nicotine-stimulated Ca 2ϩ influx, suggesting persistent desensitization or inactivation of receptors at the plasma membrane occurred. Given the differences observed between hippocampus and diencephalon neurons exposed to nicotine, multiple mechanisms may play a role in the regulation of nAChR expression and function

Chronic Nicotine Cell Specifically Upregulates Functional α4* Nicotinic Receptors: Basis for Both Tolerance in Midbrain and Enhanced Long-Term Potentiation in Perforant Path

Understanding effects of chronic nicotine requires identifying the neurons and synapses whose responses to nicotine itself, and to endogenous acetylcholine, are altered by continued exposure to the drug. To address this problem, we developed mice whose α4 nicotinic receptor subunits are replaced by normally functioning fluorescently tagged subunits, providing quantitative studies of receptor regulation at micrometer resolution. Chronic nicotine increased α4 fluorescence in several regions; among these, midbrain and hippocampus were assessed functionally. Although the midbrain dopaminergic system dominates reward pathways, chronic nicotine does not change α4* receptor levels in dopaminergic neurons of ventral tegmental area (VTA) or substantia nigra pars compacta. Instead, upregulated, functional α4* receptors localize to the GABAergic neurons of the VTA and substantia nigra pars reticulata. In consequence, GABAergic neurons from chronically nicotine-treated mice have a higher basal firing rate and respond more strongly to nicotine; because of the resulting increased inhibition, dopaminergic neurons have lower basal firing and decreased response to nicotine. In hippocampus, chronic exposure to nicotine also increases α4* fluorescence on glutamatergic axons of the medial perforant path. In hippocampal slices from chronically treated animals, acute exposure to nicotine during tetanic stimuli enhances induction of long-term potentiation in the medial perforant path, showing that the upregulated α4* receptors in this pathway are also functional. The pattern of cell-specific upregulation of functional α4* receptors therefore provides a possible explanation for two effects of chronic nicotine: sensitization of synaptic transmission in forebrain and tolerance of dopaminergic neuron firing in midbrain

Implementation of a Renal Precision Medicine Program: Clinician Attitudes and Acceptance

A precision health initiative was implemented across a multi-hospital health system, wherein a panel of genetic variants was tested and utilized in the clinical care of chronic kidney disease (CKD) patients. Pharmacogenomic predictors of antihypertensive response and genomic predictors of CKD were provided to clinicians caring for nephrology patients. To assess clinician knowledge, attitudes, and willingness to act on genetic testing results, a Likert-scale survey was sent to and self-administered by these nephrology providers (N = 76). Most respondents agreed that utilizing pharmacogenomic-guided antihypertensive prescribing is valuable (4.0 ± 0.7 on a scale of 1 to 5, where 5 indicates strong agreement). However, the respondents also expressed reluctance to use genetic testing for CKD risk stratification due to a perceived lack of supporting evidence (3.2 ± 0.9). Exploratory sub-group analyses associated this reluctance with negative responses to both knowledge and attitude discipline questions, thus suggesting reduced exposure to and comfort with genetic information. Given the evolving nature of genomic implementation in clinical care, further education is warranted to help overcome these perception barriers

Multiple DNA-binding sites in Tetrahymena telomerase

Telomerase is a ribonucleoprotein enzyme that maintains chromosome ends through de novo addition of telomeric DNA. The ability of telomerase to interact with its DNA substrate at sites outside its catalytic centre (‘anchor sites’) is important for its unique ability to undergo repeat addition processivity. We have developed a direct and quantitative equilibrium primer-binding assay to measure DNA-binding affinities of regions of the catalytic protein subunit of recombinant Tetrahymena telomerase (TERT). There are specific telomeric DNA-binding sites in at least four regions of TERT (the TEN, RBD, RT and C-terminal domains). Together, these sites contribute to specific and high-affinity DNA binding, with a Kd of ∼8 nM. Both the Km and Kd increased in a stepwise manner as the primer length was reduced; thus recombinant Tetrahymena telomerase, like the endogenous enzyme, contains multiple anchor sites. The N-terminal TEN domain, which has previously been implicated in DNA binding, shows only low affinity binding. However, there appears to be cooperativity between the TEN and RNA-binding domains. Our data suggest that different DNA-binding sites are used by the enzyme during different stages of the addition cycle