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Aim: This study explored whether inherited variants in genes causing the hereditary neuropathy condition Charcot-Marie-Tooth disease are associated with sensitivity to paclitaxel-induced peripheral neuropathy (PN). Patients & methods: Hereditary neuropathy genes previously associated with risk of paclitaxel-induced PN were sequenced in paclitaxel-treated patients. Eight putative genetic predictors in five hereditary neuropathy genes ( ARHGEF10 , SBF2 , FGD4 , FZD3  and NXN ) were tested for association with PN sensitivity after accounting for systemic exposure and clinical variables. Results: FZD3 rs7833751, a proxy for rs7001034, decreased PN sensitivity (additive model, β = -0.41; 95% CI: -0.66 to -0.17; p = 0.0011). None of the other genetic predictors were associated with PN sensitivity. Conclusion: Our results support prior evidence that FZD3 rs7001034 is protective of PN and may be useful for individualizing paclitaxel treatment to prevent PN.

Background: Childhood trauma has been linked to neuropathic pain in noncancer populations, but its relationship with cancer treatment-related neuropathic pain is unknown., Objective: This secondary data analysis of a prospective, longitudinal, observational study aimed to explore the relationship of childhood trauma experience with pain severity, pain interference, and neuropathic symptom severity (NSS) 12 months after surgery in women receiving treatment for stage 0 to III breast cancer., Methods: Women (N = 44) recruited from a comprehensive cancer center self-reported childhood trauma experience, pain severity, pain interference, NSS, co-occurring symptoms, and pain beliefs via questionnaires. Descriptive statistics were used to describe childhood trauma experience. Linear regression was used to model childhood trauma and other predictors on pain variables 12 months after surgery., Results: Childhood trauma predicted pain severity and pain interference 12 months after surgery (P < .05), as did baseline pain severities and helplessness-pain catastrophizing. Age predicted only NSS. Together, the best models predicted 31.6% to 40.9% of the variance in pain severities at 12 months (P < .001)., Conclusions: Childhood trauma exposure was a significant predictor of pain 12 months after breast cancer surgery and adjuvant treatment. Younger and helplessness-pain catastrophizing women are also at risk. Research is needed to identify preventive neuropathic pain interventions for high-risk women., Implications for Practice: Women receiving breast cancer treatment should proactively be assessed for childhood trauma history, possibly by using discreet previsit questionnaires. Childhood trauma survivors may be at high risk for poor pain outcomes and may benefit from tailored pain interventions.

Objectives: To determine the influence of a bootcamp training approach on students' self-efficacy for assessing, training, spotting, documenting, and performing manual and power wheelchair skills. Methods: In a pre-post design, students in their final year of an entry-to-practice master of occupational therapy program completed a two-day manual (6.5 h) and power (6.5 h) wheelchair skills bootcamp. Outcomes for self-efficacy (in assessing, training, spotting and documenting manual and power wheelchair skills; primary) and capacity (manual and power wheelchair skills; secondary) were collected at baseline and immediately after the bootcamp. Results: Participants ( n  = 44) were 27.3 ± 4.3 years of age (41 female). Most students (81.8%) reported little previous experience using manual and power wheelchairs at baseline. Students' self-efficacy for assessing, training, spotting, and documenting manual and power wheelchair skills improved by between 28.4% and 35.3%, representing a change from 'somewhat confident' to 'fairly confident'. Students' manual and power wheelchair skills capacity increased by 47.2% and 37.1% respectively. Conclusions: Wheelchair skills training bootcamps may help prepare occupational therapy students to assess, train, spot, and document manual and power wheelchair skills of future clients, while improving students' wheelchair skills capacity; thus may provide an option for integrating wheelchair skills training into the curriculum of time-intensive programs.Implications for rehabiliationA two-day condensed wheelchair skills training workshop improves occupational therapystudents' self-efficacy for assessing, training, spotting and documenting power andmanual wheelchair skills.A two-day condensed wheelchair skills training workshop improves occupationaltherapy students' power and manual wheelchair skills.Self-efficacy is an indicator of future behaviours. Therefore, improving students' selfefficacyfor assessing training and documenting wheelchair skills may influence their future practice.

Objective: To review assessment and management approaches for chemotherapy-induced peripheral neuropathy-related physical function deficits., Data Sources: Peer-reviewed articles from PubMed, Ovid MEDLINE, CINAHL PsycINFO, SPORTDiscus, Scopus, and key studies' reference lists., Conclusion: Brief clinical tests (eg, gait, Timed Up and Go) can screen for neuropathy-related physical function deficits. Exercise and physical therapy may be promising treatments, but the efficacy and optimal dose of such treatments for chemotherapy-induced peripheral neuropathy are unclear., Implications for Nursing Practice: Screening and assessment of neuropathy-associated physical function deficits should occur throughout neurotoxic chemotherapy treatment. If such deficits are identified, referral for rehabilitation (ie, physical or occupational therapy) and/or exercise interventions is warranted., Competing Interests: Conflict of Interest None., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Telomeres are protein-DNA complexes that protect chromosome ends from illicit ligation and resection. Telomerase is a ribonucleoprotein enzyme that synthesizes telomeric DNA to counter telomere shortening. Human telomeres are composed of complexes between telomeric DNA and a six-protein complex known as shelterin. The shelterin proteins TRF1 and TRF2 provide the binding affinity and specificity for double-stranded telomeric DNA, while the POT1-TPP1 shelterin subcomplex coats the single-stranded telomeric G-rich overhang that is characteristic of all our chromosome ends. By capping chromosome ends, shelterin protects telomeric DNA from unwanted degradation and end-to-end fusion events. Structures of the human shelterin proteins reveal a network of constitutive and context-specific interactions. The shelterin protein-DNA structures reveal the basis for both the high affinity and DNA sequence specificity of these interactions, and explain how shelterin efficiently protects chromosome ends from genome instability. Several protein-protein interactions, many provided by the shelterin component TIN2, are critical for upholding the end-protection function of shelterin. A survey of these protein-protein interfaces within shelterin reveals a series of "domain-peptide" interactions that allow for efficient binding and adaptability towards new functions. While the modular nature of shelterin has facilitated its part-by-part structural characterization, the interdependence of subunits within telomerase has made its structural solution more challenging. However, the exploitation of several homologs in combination with recent advancements in cryo-EM capabilities has led to an exponential increase in our knowledge of the structural biology underlying telomerase function. Telomerase homologs from a wide range of eukaryotes show a typical retroviral reverse transcriptase-like protein core reinforced with elements that deliver telomerase-specific functions including recruitment to telomeres and high telomere-repeat addition processivity. In addition to providing the template for reverse transcription, the RNA component of telomerase provides a scaffold for the catalytic and accessory protein subunits, defines the limits of the telomeric repeat sequence, and plays a critical role in RNP assembly, stability, and trafficking. While a high-resolution definition of the human telomerase structure is only beginning to emerge, the quick pace of technical progress forecasts imminent breakthroughs in this area. Here, we review the structural biology surrounding telomeres and telomerase to provide a molecular description of mammalian chromosome end protection and end replication.

Telomerase catalyzes telomeric DNA synthesis at chromosome ends to allow for continued cell division. The telomeric protein TPP1 is essential for enhancing the processivity of telomerase and recruiting the enzyme to telomeres. The telomerase interaction surface on human TPP1 has been mapped to 2 regions of the N-terminal oligosaccharide/oligonucleotide-binding (OB) domain, namely the TPP1 glutamate (E) and leucine (L)-rich (TEL) patch and the N terminus of TPP1-oligosaccharide/oligonucleotide-binding (NOB) region. To map the telomerase side of the interface, we exploited the predicted structural similarities for human and Tetrahymena thermophila telomerase as well as the species specificity of human and mouse telomerase for their cognate TPP1 partners. We show that swapping in the telomerase essential N-terminal (TEN) and insertions in fingers domain (IFD)-TRAP regions of the human telomerase catalytic protein subunit TERT into the mouse TERT backbone is sufficient to bias the species specificity toward human TPP1. Employing a structural homology-based mutagenesis screen focused on surface residues of the TEN and IFD regions, we identified TERT residues that are critical for contacting TPP1 but dispensable for other aspects of telomerase structure or function. We present a functionally validated structural model for how human telomerase engages TPP1 at telomeres, setting the stage for a high-resolution structure of this interface.

We report design and experimental verification of narrowband mid-infrared optical filters with transmission characteristics that are practically constant over a wide range of incident angles. The filter employs a dense array of dielectric resonant cavities in a metal film, where the transmission of each cavity depends upon localized rather than travelling fields, making the filter fundamentally angle-independent. We show experimentally a transmission around 90% from normal incidence up to 60°. Simulations show that the filter becomes polarization-independent when geometry of the cavities is azimuthally symmetric.

Persistent cell migration can occur due to anisotropy in the extracellular matrix (ECM), the gradient of a chemo-effector, or a combination of both. Through a variety of in vitro platforms, the contributions of either stimulus have been extensively studied, while the combined effect of both cues remains poorly described. Here, we report an integrative microfluidic chemotaxis assay device that enables the study of single cell chemotaxis on ECM-mimicking, aligned, and suspended nanofibers. Using this assay, we evaluated the effect of fiber spacing on the morphology and chemotaxis response of embryonic murine NIH/3T3 fibroblasts in the presence of temporally invariant, linear gradients of platelet-derived growth factor-BB (PDGF-BB). We found that the strength of PDGF-mediated chemotaxis response depends on not only the gradient slope but also the cell morphology. Low aspect ratio (3.4 ± 0.2) cells on flat substrata exhibited a chemotaxis response only at a PDGF-BB gradient of 0-10 ng mL -1 . However, high aspect ratio (19.1 ± 0.7) spindle-shaped cells attached to individual fibers exhibited maximal chemotaxis response at a ten-fold shallower gradient of 0-1 ng mL -1 , which was robustly maintained up to 0-10 ng mL -1 . Quadrilateral-shaped cells of intermediate aspect ratio (13.6 ± 0.8) attached to two fibers exhibited a weaker response compared to the spindle-shaped cells, but still stronger compared to cells attached to 2D featureless substrata. Through pharmacological inhibition, we show that the mesenchymal chemotaxis pathway is conserved in cells on fibers. Altogether, our findings show that chemotaxis on ECM-mimicking fibers is modulated by fiber spacing-driven cell shape and can be significantly different from the behavior observed on flat 2D substrata. We envisage that this microfluidic platform will have wide applicability in understanding the combined role of ECM architecture and chemotaxis in physiological and pathological processes.

Importance: Powered wheelchairs provide independence for people with mobility impairments; however, current training practices may not meet the needs of those with cognitive impairments. Shared-control teleoperation may have utility in a clinical setting when developing training suited to this population., Objective: To explore the clinical utility of a shared-control teleoperation device for powered wheelchair assessment and training., Design: In this qualitative study, we used two sequential semistructured interviews conducted a minimum of 2 wk apart. Thematic analyses were used with member checking, reflexive journaling, and triangulation of researchers to establish trustworthiness of the data., Setting: Rehabilitation center and residential care and community settings., Participants: Using purposive sampling, we recruited occupational therapists and physical therapists who were mostly female and who had a range of practice experience., Results: Fifteen participants were interviewed, and two primary themes were identified: (1) "A big enabler" described how shared control provides opportunities to train people who may otherwise be denied powered mobility, and (2) "changing the learner experience" described how shared control may promote success in skill development through an alternative learning experience., Conclusions and Relevance: Shared-control technology may have the potential to broaden the scope of therapeutic intervention by reducing risk to the driver and others in the environment and by facilitating alternative training approaches., What This Article Adds: Technological advances that allow more control over a powered wheelchair by a clinician, known as shared control, may provide learning opportunities for people who are otherwise denied access to powered mobility. Shared control may also allow the use of new instructional techniques, increase safety in the training process, and reduce anxiety associated with learning., (Copyright © 2019 by the American Occupational Therapy Association, Inc.)

There are no estimates of the heritability of phenotypic udder traits in suckler sheep, which produce meat lambs, and whether these are associated with resilience to mastitis. Mastitis is a common disease which damages the mammary gland and reduces productivity. The aims of this study were to investigate the feasibility of collecting udder phenotypes, their heritability and their association with mastitis in suckler ewes. Udder and teat conformation, teat lesions, intramammary masses (IMM) and litter size were recorded from 10 Texel flocks in Great Britain between 2012 and 2014; 968 records were collected. Pedigree data were obtained from an online pedigree recording system. Univariate quantitative genetic parameters were estimated using animal and sire models. Linear mixed models were used to analyse continuous traits and generalised linear mixed models were used to analyse binary traits. Continuous traits had higher heritabilities than binary with teat placement and teat length heritability (h 2) highest at 0.35 (SD 0.04) and 0.42 (SD 0.04), respectively. Udder width, drop and separation heritabilities were lower and varied with udder volume. The heritabilities of IMM and teat lesions (sire model) were 0.18 (SD 0.12) and 0.17 (SD 0.11), respectively. All heritabilities were sufficiently high to be in a selection programme to increase resilience to mastitis in the population of Texel sheep. Further studies are required to investigate genetic relationships between traits and to determine whether udder traits predict IMM, and the potential benefits from including traits in a selection programme to increase resilience to chronic mastitis.

Single-molecule localization microscopy (SMLM) is a rapidly evolving technique to resolve subcellular structures and single-molecule dynamics at the nanoscale. Here, we employ conventional BODIPY conjugates for live-cell SMLM via their previously reported red-shifted ground-state dimers (D II ), which transiently form through bi-molecular encounters and emit bright single-molecule fluorescence. We employ the versatility of D II -state SMLM to resolve the nanoscopic spatial regulation and dynamics of single fatty acid analogs (FAas) and lipid droplets (LDs) in living yeast and mammalian cells with two colors. In fed cells, FAas localize to the endoplasmic reticulum and LDs of ~125 nm diameter. Upon fasting, however, FAas form dense, non-LD clusters of ~100 nm diameter at the plasma membrane and transition from free diffusion to confined immobilization. Our reported SMLM capability of conventional BODIPY conjugates is further demonstrated by imaging lysosomes in mammalian cells and enables simple and versatile live-cell imaging of sub-cellular structures at the nanoscale.

We develop and employ the Fluorescence-Activating and absorption-Shifting Tag (FAST) system for super-resolution (SR) imaging and single-molecule tracking based on single-molecule localizations. The fast off rate of fluorogen binding, combined with its spatially well-separated labeling of the densely expressed FAST fusion proteins, allowed single-molecule measurements to be performed in both living and fixed cells. The well-separated fluorescence localization density was achieved by either reversibly controlling the fluorogen concentration or by irreversibly photobleaching the FAST-fluorogen complex. The experimentally determined resolution of 28 nm allowed us to resolve Ensconsin-labeled microtubules and to track single molecules in mitochondria. Our results demonstrate that FAST is well-suited for single-molecule localization microscopy (SMLM). The small size and the availability of spectrally distinct fluorogens present unique advantages of the FAST system as a potential orthogonal labeling strategy that could be applied in conjunction with existing super-resolution dyes and photoactivatable proteins in versatile imaging applications.

Background.: Powered-wheelchair use improves participation for people with mobility limitations; however, many individuals do not receive powered-wheelchair skills training that meets their learning needs., Purpose.: The aim of this work is to evaluate the feasibility of a powered-wheelchair training program for older adults with cognitive impairment, using errorless learning strategies facilitated by shared control technology., Method.: A feasibility 2 × 2 factorial randomized controlled trial will recruit 32 older adults in residential care with mild to moderate cognitive impairment who are new powered-wheelchair use. The intervention consists of six or 12 training sessions, facilitated by shared control technology, using errorless learning techniques. Control participants will receive six or 12 training sessions using trial-and-error methods. Feasibility and clinical outcomes data (primary outcome: powered-wheelchair skills) will be collected., Implications.: Errorless learning facilitated by shared control technology may be an alternative to meet the powered-wheelchair learning needs of older adults with cognitive impairments.

Neutron scattering measurements on the pyrochlore magnet Ce&#95;{2}Zr&#95;{2}O&#95;{7} reveal an unusual crystal field splitting of its lowest J=5/2 multiplet, such that its ground-state doublet is composed of m&#95;{J}=±3/2, giving these doublets a dipole-octupole (DO) character with local Ising anisotropy. Its magnetic susceptibility shows weak antiferromagnetic correlations with θ&#95;{CW}=-0.4(2)  K, leading to a naive expectation of an all-in, all-out ordered state at low temperatures. Instead, our low-energy inelastic neutron scattering measurements show a dynamic quantum spin ice state, with suppressed scattering near |Q|=0, and no long-range order at low temperatures. This is consistent with recent theory predicting symmetry-enriched U(1) quantum spin liquids for such DO doublets decorating the pyrochlore lattice. Finally, we show that disorder, especially oxidation of powder samples, is important in Ce&#95;{2}Zr&#95;{2}O&#95;{7} and could play an important role in the low-temperature behavior of this material.

Objectives: The aim of this study was to evaluate the internal consistency, test-retest reliability and responsiveness of the Self-Efficacy in Assessing, Training and Spotting manual wheelchair skills (SEATS-M) and Self-Efficacy in Assessing, Training and Spotting power wheelchair skills (SEATS-P)., Methods: A 2-week test-retest design was used with a convenience sample of occupational and physical therapists who worked at a provincial rehabilitation centre (inpatient and outpatient services). Sixteen participants completed the SEATS-M and 18 participants completed the SEATS-P., Results: For the SEATS-M assessment, training, spotting and documentation sections, Cronbach's alpha coefficients ranged from 0.90 to 0.97, the 2-week intraclass correlation coefficients (ICC 1,1 ) ranged from 0.81 to 0.95, the standard error of measurements (SEM) ranged from 5.06 to 8.70 and the smallest real differences (SRD) ranged from 6.24 to 8.18. For the SEATS-P assessment, training, spotting and documentation sections, Cronbach's alpha coefficients ranged from 0.83 to 0.92, the ICCs ranged from 0.72 to 0.86, the SEMs ranged from 4.54 to 8.91 and the SRDs ranged from 5.90 to 8.27., Conclusions: There is preliminary evidence that both the SEATS-M and the SEATS-P have high internal consistency, good test-retest reliability and support for responsiveness. These tools can be used in evaluating clinician self-efficacy with assessing, training, spotting and documenting wheelchair skills included on the Wheelchair Skills Test. Implications for Rehabilitation There is preliminary evidence that the SEATS-M and SEATS-P are reliable and responsive outcome measures that can be used to evaluate the self-efficacy of clinicians to administer the Wheelchair Skills Program. Measurement of clinicians' self-efficacy in this area of practice may enable an enhanced understanding of the areas in which clinicians lack self-efficacy, thereby informing the development of improved knowledge translation interventions.

Adrenal chromaffin cells and sympathetic neurons synthesize and release catecholamines, and both cell types are derived from neural crest precursors. However, they have different developmental histories, with sympathetic neurons derived directly from neural crest precursors while adrenal chromaffin cells arise from neural crest-derived cells that express Schwann cell markers. We have sought to identify the genes, including imprinted genes, which regulate the development of the two cell types in mice. We developed a method of separating the two cell types as early as E12.5, using differences in expression of enhanced yellow fluorescent protein driven from the tyrosine hydroxylase gene, and then used RNA sequencing to confirm the characteristic molecular signatures of the two cell types. We identified genes differentially expressed by adrenal chromaffin cells and sympathetic neurons. Deletion of a gene highly expressed by adrenal chromaffin cells, NIK-related kinase, a gene on the X-chromosome, results in reduced expression of adrenaline-synthesizing enzyme, phenyl-N-methyl transferase, by adrenal chromaffin cells and changes in cell cycle dynamics. Finally, many imprinted genes are up-regulated in chromaffin cells and may play key roles in their development.

Introduction: In a pilot study of chronic maternal hyperoxygenation (CMH) in left heart hypoplasia (LHH), we sought to determine effect estimates of CMH on head size, vascular resistance indices, and neurodevelopment compared to controls., Material and Methods: Nine gravidae meeting the inclusion criteria (fetal LHH, ≥25.9 weeks' gestation, and ≥10% increase in percent aortic flow after acute hyperoxygenation) were prospectively enrolled. Controls were 9 contemporary gravidae with fetal LHH without CMH. Brain growth and Doppler-derived estimates of fetal cerebrovascular and placental resistance were blindly evaluated and compared using longitudinal regression. Postnatal anthropomorphic and neurodevelopmental assessments were compared., Results: There was no difference in baseline fetal measures between groups. There was significantly slower biparietal diameter (BPD) growth in the CMH group (z-score change -0.03 ± 0.02 vs. +0.09 ± 0.05 units/week, p = 0.02). At 6 months postnatal age, the mean head circumference z-score in the CMH group was smaller than that of controls (-0.20 ± 0.58 vs. +0.85 ± 1.11, p = 0.048). There were no differences in neurodevelopmental testing at 6 and 12 months., Discussion: In this pilot study, relatively diminished fetal BPD growth and smaller infant head circumference z-scores at 6 months were noted with in utero CMH exposure., (© 2018 S. Karger AG, Basel.)

Background: Adolescence represents a period of vulnerability to affective disorders. Neuroticism is considered a heritable risk factor for depression, but is not directly amenable to intervention. Therefore, it is important to identify the contributions of modifiable risk factors. Negative cognitive biases are implicated in the onset and maintenance of affective disorders in adults, and may represent modifiable risk factors in adolescence., Aim(s): This study sought to assess to what extent cognitive biases are able to predict depression, anxiety and wellbeing beyond that of neuroticism in adolescents., Methods: Adolescents (N = 99), recruited from Scottish secondary schools (54.5% female; mean age = 14.7), ensured a sample representing the breadth of the mental health spectrum. In line with prevalence estimates, 18% of this sample demonstrated clinical levels of depression symptoms. Cognitive biases of autobiographical memory, self-referential memory, ambiguous scenarios interpretation, facial expression recognition, rumination and dysfunctional attitudes were assessed. Depression, anxiety, and wellbeing were indexed using the Mood and Feelings Questionnaire, Spence Children's Anxiety Scale and the BBC Subjective Wellbeing Scale., Results: Regression analyses demonstrated neuroticism to significantly predict depression, anxiety and wellbeing. The addition of cognitive biases resulted in a significant increase of explained variance with final models explaining just over 50% of variances of depression, anxiety and wellbeing., Conclusion: These findings demonstrate that cognitive biases explain mental health symptoms over and above that of neuroticism. Depressive symptomology was particularly related to self-referential memory bias, while anxiety was predicted by interpretive bias. The key clinical implication is that targeting specific biases based on diagnostic features may be of particular benefit in alleviating distress and promoting wellbeing., (Copyright © 2018. Published by Elsevier B.V.)

We and others previously showed that in mouse embryos lacking the transcription factor Sox10, olfactory ensheathing cell (OEC) differentiation is disrupted, resulting in defective olfactory axon targeting and fewer gonadotropin-releasing hormone (GnRH) neurons entering the embryonic forebrain. The underlying mechanisms are unclear. Here, we report that OECs in the olfactory nerve layer express Frzb-encoding a secreted Wnt inhibitor with roles in axon targeting and basement membrane breakdown-from embryonic day (E)12.5, when GnRH neurons first enter the forebrain, until E16.5, the latest stage examined. The highest levels of Frzb expression are seen in OECs in the inner olfactory nerve layer, abutting the embryonic olfactory bulb. We find that Sox10 is required for Frzb expression in OECs, suggesting that loss of Frzb could explain the olfactory axon targeting and/or GnRH neuron migration defects seen in Sox10-null mice. At E16.5, Frzb-null embryos show significant reductions in both the volume of the olfactory nerve layer expressing the maturation marker Omp and the number of Omp-positive olfactory receptor neurons in the olfactory epithelium. As Omp upregulation correlates with synapse formation, this suggests that Frzb deletion indeed disrupts olfactory axon targeting. In contrast, GnRH neuron entry into the forebrain is not significantly affected. Hence, loss of Frzb may contribute to the olfactory axon targeting phenotype, but not the GnRH neuron phenotype, of Sox10-null mice. Overall, our results suggest that Frzb secreted from OECs in the olfactory nerve layer is important for olfactory axon targeting., (© 2018 The Authors. Glia published by Wiley Periodicals, Inc.)

Mouse urinary behavior is quantifiable and is used to pinpoint mechanisms of voiding dysfunction and evaluate potential human therapies. Approaches to evaluate mouse urinary function vary widely among laboratories, however, complicating cross-study comparisons. Here, we describe development and multi-institutional validation of a new tool for objective, consistent, and rapid analysis of mouse void spot assay (VSA) data. Void Whizzard is a freely available software plugin for FIJI (a distribution of ImageJ) that facilitates VSA image batch processing and data extraction. We describe its features, demonstrate them by evaluating how specific VSA method parameters influence voiding behavior, and establish Void Whizzard as an expedited method for VSA analysis. This study includes control and obese diabetic mice as models of urinary dysfunction to increase rigor and ensure relevance across distinct voiding patterns. In particular, we show that Void Whizzard is an effective tool for quantifying nonconcentric overlapping void spots, which commonly confound analyses. We also show that mouse genetics are consistently more influential than assay design parameters when it comes to VSA outcomes. None of the following procedural modifications to reduce overlapping spots masked these genetic-related differences: reduction of VSA testing duration, water access during the assay period, placement of a wire mesh cage bottom on top of or elevated over the filter paper, treatment of mesh with a hydrophobic spray, and size of wire mesh opening. The Void Whizzard software and rigorous validation of VSA methodological parameters described here advance the goal of standardizing mouse urinary phenotyping for comprehensive urinary phenome analyses.

Lack of activation in self-care can compromise a patient's ability to monitor and manage cancer treatment-related side effects, such as chemotherapy-induced peripheral neuropathy (CIPN). The web-based Carevive® Care Planning System (CPS) was developed to promote evidence-based symptom assessment and treatment by enhancing patients' involvement in their own care. The purpose of this single-arm, pre-test/post-test, prospective study was to examine whether the CPS can promote patient activation in CIPN symptom assessment and management. Seventy-five women with breast cancer receiving neurotoxic chemotherapy were recruited from a Comprehensive Cancer Center. Using standardized neuropathy measures embedded within the CPS, patients reported their CIPN symptoms over three consecutive clinical visits and completed the Patient Activation Measure (PAM) at the first and third visits. Mean changes in PAM scores between visits were compared using repeated measure analysis of covariance, adjusting for age. At baseline, patients were diagnosed with cancer within the past year (94.7%), highly activated (85% Level III/IV), and had a mean age of 51.3. PAM scores improved significantly from 67.15 (SD = 13.5; range = 47-100) at visit one to 69.29 (SD = 16.18; range = 47-100) (p = 0.02) (n = 62) at visit three. However, patients perceived the CPS to be of minimal value because it solely focused on CIPN and, for many, CIPN was not severe enough to motivate them to seek out symptom management information. Further research is needed to assess the utility of the CPS in promoting activation in the assessment and management of varying cancer treatment-related symptoms.

Longitudinal studies are warranted to clarify the influence crime has on health outcomes in children especially children representing multiple racial/ethnic backgrounds. To address this need, the current study examined whether neighborhood-level crime predicted changes in body mass index z (BMIz) scores in 373 White (W), 627 African American (AA), 1020 Hispanic (H), and 88 Asian (A), five to ten year-old boys and girls living in urban neighborhoods. Heights and weights were assessed at baseline (2012) and three-years later and used to calculate BMIz scores. Characteristics of zip codes where students lived during the three-year period were obtained at baseline from various sources. The Crime Risk Index (CRI) for each zip code was calculated using actual crime statistics. Multiple linear regression analyses were conducted to examine associations between baseline CRI and follow-up BMIz scores while controlling for other variables including BMIz at baseline. The CRI and BMIz scores differed significantly by race/ethnicity with the highest values for both noted in H. Regression analyses indicated that the CRI accounted for a significant percentage of the variance in follow-up BMIz scores in the overall sample. When race/ethnicity was considered, the CRI predicted follow-up BMIz scores only in W children. The CRI was not significantly associated with BMIz scores in the other races/ethnicities. The impact actual, neighborhood-level crime has on BMI in children is complex. Based on the existing evidence, considering actual crime as a primary target in obesity prevention would be premature especially in racial/ethnicity minority children living in urban areas.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially dose-limiting side effect of neurotoxic chemotherapies. No therapies are available to prevent CIPN. The small number of positive randomized clinical trials (RCTs) evaluating preventive therapies for CIPN provide little guidance to inform the design of future trials. Moreover, the lack of consensus regarding major design features in this area poses challenges to development of new therapies. An Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION)-Consortium on Clinical Endpoints and Procedures for Peripheral Neuropathy Trials (CONCEPPT) meeting attended by neurologists, oncologists, pharmacists, clinical trialists, statisticians, and regulatory experts was convened to discuss design considerations and provide recommendations for CIPN prevention trials. This article outlines considerations related to design of RCTs that evaluate preventive therapies for CIPN including (1) selection of eligibility criteria (e.g., cancer types, chemotherapy types, inclusion of preexisting neuropathy); (2) selection of outcome measures and endpoints, including those that incorporate alterations in chemotherapy dosing, which may affect the rate of CIPN development and its severity; (3) potential effects of the investigational therapy on the efficacy of chemotherapy; and (4) sample size estimation. Our hope is that attention to the design considerations and recommendations outlined in this article will improve the quality and assay sensitivity of CIPN prevention trials and thereby accelerate the identification of efficacious therapies., (© 2018 American Academy of Neurology.)

Purpose: Paclitaxel exposure, specifically the maximum concentration ( C max ) and amount of time the concentration remains above 0.05 μmol/L ( T c >0.05 ), has been associated with the occurrence of paclitaxel-induced peripheral neuropathy. The objective of this study was to validate the relationship between paclitaxel exposure and peripheral neuropathy. Experimental Design: Patients with breast cancer receiving paclitaxel 80 mg/m 2 × 12 weekly doses were enrolled in an observational clinical study (NCT02338115). Paclitaxel plasma concentration was measured at the end of and 16-26 hours after the first infusion to estimate C max and T c >0.05 Patient-reported peripheral neuropathy was collected via CIPN20 at each dose, and an 8-item sensory subscale (CIPN8) was used in the primary analysis to test for an association with T c >0.05 Secondary analyses were conducted using C max as an alternative exposure parameter and testing each parameter with a secondary endpoint of the occurrence of peripheral neuropathy-induced treatment disruption. Results: In 60 subjects included in the analysis, the increase in CIPN8 during treatment was associated with baseline CIPN8, cumulative dose, and relative dose intensity ( P < 0.05), but neither T c >0.05 ( P = 0.27) nor C max ( P = 0.99). In analyses of the secondary endpoint, cumulative dose (OR = 1.46; 95% confidence interval (CI), 1.18-1.80; P = 0.0008) and T c >0.05 (OR = 1.79; 95% CI, 1.06-3.01; P = 0.029) or C max (OR = 2.74; 95% CI, 1.45-5.20; P = 0.002) were associated with peripheral neuropathy-induced treatment disruption. Conclusions: Paclitaxel exposure is predictive of the occurrence of treatment-limiting peripheral neuropathy in patients receiving weekly paclitaxel for breast cancer. Studies are warranted to determine whether exposure-guided dosing enhances treatment effectiveness and/or prevents peripheral neuropathy in these patients. Clin Cancer Res; 24(15); 3602-10. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Geological pathways for the recycling of Earth's surface materials into the mantle are both driven and obscured by plate tectonics 1-3 . Gauging the extent of this recycling is difficult because subducted crustal components are often released at relatively shallow depths, below arc volcanoes 4-7 . The conspicuous existence of blue boron-bearing diamonds (type IIb) 8,9 reveals that boron, an element abundant in the continental and oceanic crust, is present in certain diamond-forming fluids at mantle depths. However, both the provenance of the boron and the geological setting of diamond crystallization were unknown. Here we show that boron-bearing diamonds carry previously unrecognized mineral assemblages whose high-pressure precursors were stable in metamorphosed oceanic lithospheric slabs at depths reaching the lower mantle. We propose that some of the boron in seawater-serpentinized oceanic lithosphere is subducted into the deep mantle, where it is released with hydrous fluids that enable diamond growth 10 . Type IIb diamonds are thus among the deepest diamonds ever found and indicate a viable pathway for the deep-mantle recycling of crustal elements.

Purpose: To determine if older adult, novice wheelchair users who drive a power wheelchair with a JoyBar control complete maneuverability tasks in less time and with less error than those who drive a power wheelchair with a standard joystick control., Materials and Methods: A parallel randomized controlled trial design conducted at a medical rehabilitation and research centre with ambulatory older adults aged 60 and above (n = 27). The intervention was the JoyBar alternative wheelchair control. The primary outcome measure was total time to complete each of the two maneuverability tasks. The secondary outcome measure was total number of errors during each of the maneuverability tasks., Results: An independent, two sampled t-test was conducted and revealed that the JoyBar group took a greater amount of time to complete both maneuverability tasks than the control group (p < .05). No significant differences (p < .05) were found in rates of error on either task between the JoyBar and joystick groups., Conclusions: Maneuverability of a powered wheelchair by novice wheelchair users was not improved through the use of the JoyBar when compared to a standard wheelchair joystick, as measured by rates of error and time to complete maneuverability tasks. Implications for rehabilitation Clients who are new to powered wheelchair use may perform maneuverability tasks faster, with equivalent accuracy, using a standard joystick versus the JoyBar. Clients who use a JoyBar may require adjustments to the programming of their wheelchair to ensure optimal performance. Additional training may be required to achieve proficiency in maneuverability tasks with a JoyBar versus a standard joystick.

Objectives: To explore associations between quantitative sensory testing (QST) and pretreatment pain, physical, and psychological characteristics in women with breast cancer., Sample & Setting: 41 women with treatment-naive stage 0-III breast cancer at the University of Michigan Comprehensive Cancer Center in Ann Arbor., Methods & Variables: Participants completed self-report surveys and QST within the month before breast surgery. Pressure pain thresholds (PPTs) were measured bilaterally at each trapezius with a manual QST algometer. PPT values were split, yielding low, moderate, and high pain sensitivity subgroups. Subgroup self-reported characteristics were compared using Spearman's correlation, chi-square, and one-way analysis of variance., Results: Lower PPT (higher sensitivity) was associated with higher levels of pain interference and maladaptive pain cognitions. The high-sensitivity group reported higher pain severities, interference, and catastrophizing and lower belief in internal locus of pain control than the low-sensitivity group., Implications for Nursing: Individualized interventions for maladaptive pain cognitions before surgery may reduce pain sensitivity and the severity of chronic pain developed after surgery.

Background: Mobility limitations represent the third most prevalent cause of disability, affecting more than 1.9 million community-dwelling Canadians. Walking aids are often prescribed to reduce the impacts of mobility impairments. There are limited data on walking aids since 2004., Objective: The objectives of this study were to investigate the prevalence of walking aid use in Canada and to explore demographic characteristics among users of walking aids., Design: The design used was a secondary analysis of a cross-sectional national survey., Methods: Data were obtained from the 2012 Canadian Survey on Disability from community-dwelling individuals who were 15 years old or older, had a self-identified activity limitation, and indicated that they used at least 1 walking aid (cane/walking stick/crutches or walker). Prevalence estimates were calculated as weighted frequencies. Analytic variables included walking aid type, sex, age, province/territory of residence, and main cause of activity limitation., Results: Approximately 1,125,000 community-dwelling individuals who were 15 years old or older used walking aids, representing 4.1% of the Canadian population. Of these individuals, 962,290 used canes/walking sticks/crutches, and 465,340 used a walker. Users of walking aids were predominantly female, with a mean age of 68 years., Limitations: Self-reported results reflect only the perceptions of individuals living in Canadian communities. Analyses excluded individuals in residential or long-term care settings and individuals living on First Nations reserves., Conclusions: Since 2004, there has been a 2% increase in the prevalence of walking aid use by the Canadian population, which is likely related to the aging of the population. The high prevalence of walking aid use highlights the need for better use of existing resources to ensure that individuals are receiving the correct devices. Results of this study suggest a need to evaluate the impact of device use to better understand how resources should be allocated for prescription and maintenance of walking aids and training of users.

Increased awareness, interest and use of assistive technology (AT) presents substantial opportunities for many citizens to become, or continue being, meaningful participants in society. However, there is a significant shortfall between the need for and provision of AT, and this is patterned by a range of social, demographic and structural factors. To seize the opportunity that assistive technology offers, regional, national and sub-national assistive technology policies are urgently required. This paper was developed for and through discussion at the Global Research, Innovation and Education on Assistive Technology (GREAT) Summit; organized under the auspices of the World Health Organization's Global Collaboration on Assistive Technology (GATE) program. It outlines some of the key principles that AT polices should address and recognizes that AT policy should be tailored to the realities of the contexts and resources available. AT policy should be developed as a part of the evolution of related policy across a number of different sectors and should have clear and direct links to AT as mediators and moderators for achieving the Sustainable Development Goals. The consultation process, development and implementation of policy should be fully inclusive of AT users, and their representative organizations, be across the lifespan, and imbued with a strong systems-thinking ethos. Six barriers are identified which funnel and diminish access to AT and are addressed systematically within this paper. We illustrate an example of good practice through a case study of AT services in Norway, and we note the challenges experienced in less well-resourced settings. A number of economic factors relating to AT and economic arguments for promoting AT use are also discussed. To address policy-development the importance of active citizenship and advocacy, the need to find mechanisms to scale up good community practices to a higher level, and the importance of political engagement for the policy process, are highlighted. Policy should be evidence-informed and allowed for evidence-making; however, it is important to account for other factors within the given context in order for policy to be practical, authentic and actionable. Implications for Rehabilitation The development of policy in the area of asssitive technology is important to provide an overarching vision and outline resourcing priorities. This paper identifies some of the key themes that should be addressed when developing or revising assistive technology policy. Each country should establish a National Assistive Technology policy and develop a theory of change for its implementation.

Background and Methods: This paper reviews the current capacity of personnel in enabling access to assistive technology (AT) as well as the systems and processes within which they work, and was reviewed, discussed, and refined during and following the Global Research, Innovation, and Education in Assistive Technology (GREAT) Summit., Findings: Key concepts addressed include a person-centred team approach; sustainability indicators to monitor, measure, and respond to needs for service design and delivery; education, research, and training for competent practice, using the six rehab-workforce challenges framework; and credentialing frameworks. We propose development of a competence framework and associated education and training programs, and development and implementation of a certification framework for AT personnel., Conclusions: There is a resolve to address the challenges faced by People globally to access assistive technology. Context specific needs assessment is required to understand the AT Personnel landscape, to shape and strengthen credentialing frameworks through competencies and certification, acknowledging both general and specific skill mix requirements. Implications for Rehabilitation Personnel in assistive technology (AT) provision should be trained using a person-centred team approach, which emphasizes appropriate skill-mix to address multiple needs within the community. Sustainability indicators should be used which allow personnel to monitor, measure and respond to needs for service design and delivery. A competence framework with associated education and training program, coupled with the development and implementation of a certification framework for AT personnel needs, will promote quality in AT personnel training globally.

The purpose of this method is to obtain high-integrity RNA samples from enteric ganglia collected from unfixed, freshly-resected human intestinal tissue using laser capture microdissection (LCM). We have identified five steps in the workflow that are crucial for obtaining RNA isolates from enteric ganglia with sufficiently high quality and quantity for RNA-seq. First, when preparing intestinal tissue, each sample must have all excess liquid removed by blotting prior to flattening the serosa as much as possible across the bottom of large base molds. Samples are then quickly frozen atop a slurry of dry ice and 2-methylbutane. Second, when sectioning the tissue, it is important to position cryomolds so that intestinal sections parallel the full plane of the myenteric plexus, thereby yielding the greatest surface area of enteric ganglia per slide. Third, during LCM, polyethylene napthalate (PEN)-membrane slides offer the greatest speed and flexibility in outlining the non-uniform shapes of enteric ganglia when collecting enteric ganglia. Fourth, for distinct visualization of enteric ganglia within sections, ethanol-compatible dyes, like Cresyl Violet, offer excellent preservation of RNA integrity relative to aqueous dyes. Finally, for the extraction of RNA from captured ganglia, we observed differences between commercial RNA extraction kits that yielded superior RNA quantity and quality, while eliminating DNA contamination. Optimization of these factors in the current protocol greatly accelerates the workflow and yields enteric ganglia samples with exceptional RNA quality and quantity.

Standard audiometric evaluations are not sensitive enough to identify hidden hearing loss (HHL) and/or cochlear synaptopathy (CS). Patients with either of these conditions frequently present with difficulty understanding speech in noise or other complaints such as tinnitus. The purpose of this systematic review is to identify articles in peer-reviewed journals that assessed the sensitivity of audiologic measures for detecting HHL and/or CS, and which showed potential for use in a clinical test battery for these disorders. A reference librarian submitted specific boolean terminology to MEDLINE, Embase, and Web of Science. The authors used a consensus approach with specially designed score sheets for the selection of titles, abstracts, and then articles for inclusion in the systematic review and for quality assessment. Fifteen articles were included in the systematic review. Seven articles involved humans; seven involved animals, and one study used both humans and animals. Results showed that pure-tone audiometry to 20 kHz, otoacoustic emissions, electrocochleography, auditory brainstem response (ABR), electrophysiological tests, speech recognition in noise with and without temporal distortion, interviews, and self-report measures have been used to assess HHL and/or CS. For HHL, ultra-high-frequency audiometry may help identify persons with sensory hair cell loss that does not show up on standard audiograms. Promising nonbehavioral measures for CS included ABR wave I amplitude, the summating potential-to-action potential ratio, and speech recognition in noise with and without temporal distortion. Self-report questionnaires also may help identify auditory dysfunction in persons with normal hearing.

Various U.S. laws, such as the Clean Air Act and the Food Quality Protection Act, require additional protections for susceptible subpopulations who face greater environmental health risks. The main ethical rationale for providing these protections is to ensure that environmental health risks are distributed fairly. In this article, we (1) consider how several influential theories of justice deal with issues related to the distribution of environmental health risks; (2) show that these theories often fail to provide specific guidance concerning policy choices; and (3) argue that an approach to public decision making known as accountability for reasonableness can complement theories of justice in establishing acceptable environmental health risks for the general population and susceptible subpopulations. Since accountability for reasonableness focuses on the fairness of the decision-making process, not the outcome, it does not guarantee that susceptible subpopulations will receive a maximum level of protection, regardless of costs or other morally relevant considerations.

Purpose: The purpose of this study is to estimate the interrater and intrarater reliability of the Wheelchair Skills Test (WST) Version 4.2 for powered wheelchairs operated by adult users., Materials and Methods: Cohort study with a convenience sample of occupational therapists (n = 10). For the main outcome measure, participants viewed and scored eight videos of adult power wheelchair users completing the 30 skills of the WST Version 4.2 on two occasions, a minimum of two weeks apart. Using these scores, we calculated intraclass correlation coefficients to estimate interrater and intrarater reliability., Results: The interrater reliability intraclass correlation coefficient was 0.940 (95%CI 0.862-0.985). Intrarater reliability intraclass correlation coefficients ranged from 0.923 to 0.998., Conclusions: The WST Version 4.2 has excellent interrater and intrarater reliability and is a reliable tool for use in clinical and research practice to evaluate a power wheelchair user's skill capacity. Implications for Rehabilitation The Wheelchair Skills Test for Powered Wheelchair Users (WST-P 4.2) is a useful addition to the clinical tools available for clinicians who assess and train for powered wheelchair use. The WST-P 4.2 has excellent reliability and potential for clinical use as a pre-post measure of powered wheelchair skills. Clinicians using the WST-P 4.2 should attempt to maintain consistent scoring procedures, particularly for those skills that may require subjective assessment of skill safety.

The error-free and efficient repair of DNA double-stranded breaks (DSBs) is extremely important for cell survival. RNA has been implicated in the resolution of DNA damage but the mechanism remains poorly understood. Here, we show that miRNA biogenesis enzymes, Drosha and Dicer, control the recruitment of repair factors from multiple pathways to sites of damage. Depletion of Drosha significantly reduces DNA repair by both homologous recombination (HR) and non-homologous end joining (NHEJ). Drosha is required within minutes of break induction, suggesting a central and early role for RNA processing in DNA repair. Sequencing of DNA:RNA hybrids reveals RNA invasion around DNA break sites in a Drosha-dependent manner. Removal of the RNA component of these structures results in impaired repair. These results show how RNA can be a direct and critical mediator of DNA damage repair in human cells.

Background: Wheelchairs, scooters, and related equipment are essential for the well-being of individuals with limited mobility and impact participation, health, and quality of life., Purpose: Our objective was to identify and evaluate policies governing equipment funding for Canadian adults. We reviewed funding legislation and program documentation for adult Canadians (≥18 years of age) covered by their provincial, territorial, or federal health care plan. Documents were obtained online or through administrative staff. Policy evaluation was guided by the Disability Policy Lens from the Canadian Disability Policy Alliance., Key Issues: Coverage ranges from full funding for all individuals within the jurisdiction to programs limited by strict eligibility criteria. Each jurisdiction defines "disability" or "basic/essential need" differently, contributing to further funding disparities., Implications: Funding policies differ substantially across Canada, resulting in unequal access to equipment dependent on province or territory. We identified eligibility, funding, definitions of mobility, repair and replacement, and prescriber requirement benchmarks that represent policy targets for improved access.

The geriatric syndromes of falls, incontinence, and osteoporosis are concerns in older adults because of their potential impact on quality of life. Asking about history of falls or a fear of falling should prompt a multifactorial assessment of fall risk and targeted interventions to reduce falls. Urinary and fecal incontinence should be screened because they are common conditions that are underreported due to embarrassment and general perception that incontinence is a normal part of aging. Women over age 65, men over age 70, and younger patients with high-risk characteristics should be screened with bone mineral density testing with dual-energy x-ray absorptiometry., (Copyright © 2017 Elsevier Inc. All rights reserved.)

One of the most significant changes to the Common Rule is the requirement that institutions use a single Institutional Review Board (IRB) for cooperative research in the United States, unless more than one IRB is required by state, local, or tribal law, or a signatory federal agency decides an exception is warranted. We surveyed Human Research Protection Program (HRPP) officials at the top U.S. research institutions to understand their knowledge and opinion of the mandate, what steps their institutions are taking, and difficulties their institutions are facing. One-hundred seven institutions (56.9%) responded to the survey. While support for the single-IRB mandate was positive overall, most respondents acknowledged that their institution is likely to face some difficulties complying with it. Regulatory agencies can help institutions to comply with the mandate by providing guidance concerning such issues as exceptions to the mandate, local context review, oversight, and implementation of reliance agreements, and development of policies, procedures, and best practices.

Background: Anemia and vitamin D deficiency are highly prevalent in critical illness, and vitamin D status has been associated with hemoglobin concentrations in epidemiologic studies. We examined the effect of high-dose vitamin D therapy on hemoglobin and hepcidin concentrations in critically ill adults., Materials and Methods: Mechanically ventilated critically ill adults (N = 30) enrolled in a pilot double-blind, randomized, placebo-controlled trial of high-dose vitamin D 3 (D 3 ) were included in this analysis. Participants were randomized to receive placebo, 50,000 IU D 3 , or 100,000 IU D 3 daily for 5 days (totaling 250,000 IU D 3 and 500,000 IU D 3 , respectively). Blood was drawn weekly throughout hospitalization for up to 4 weeks. Linear mixed-effects models were used to assess change in hemoglobin and hepcidin concentrations by treatment group over time., Results: At enrollment, >75% of participants in all groups had plasma 25-hydroxyvitamin D (25(OH)D) concentrations <30 ng/mL, and >85% of participants across groups were anemic. In the 500,000-IU D 3 group, hemoglobin concentrations increased significantly over time (P group × time = .01) compared with placebo but did not change in the 250,000-IU D 3 group (P group × time = 0.59). Hepcidin concentrations decreased acutely in the 500,000-IU D 3 group relative to placebo after 1 week (P = .007). Hepcidin did not change significantly in the 250,000-IU D 3 group., Conclusion: In these critically ill adults, treatment with 500,000 IU D 3 was associated with increased hemoglobin concentrations over time and acutely reduced serum hepcidin concentrations. These findings suggest that high-dose vitamin D may improve iron metabolism in critical illness and should be confirmed in larger studies., (© 2016 American Society for Parenteral and Enteral Nutrition.)

The autonomic and sensory nervous systems are required for proper function of all visceral organs, including the lower urinary tract (LUT). Despite the wide prevalence of bladder dysfunction, effective treatment options remain limited. Pelvic innervation regenerative strategies are promising, but surprisingly little is known about the molecular factors driving the development of bladder innervation. Given prior evidence that serotonin receptor 5-HT3A is expressed early in LUT development and is an important mediator of adult bladder function, we sought to determine if 5-HT3A is required for the development of autonomic innervation of the bladder. We found that 5-HT3A is expressed early in fetal mouse pelvic ganglia and is maintained through adulthood. Htr3a knockout male mice, but not females, exhibit increased urinary voiding frequency compared to wild type littermates. Analysis of LUT function via anesthetized cystometry revealed decreased voiding efficiency in male Htr3a mutants. Htr3a -/- mutant animals exhibit a transient disturbance of autonomic neuronal subtype markers (tyrosine hydroxylase and choline acetyl transferase) within the fetal pelvic ganglia, although the imbalance of neuronal subtype markers assayed is no longer apparent in adulthood. Loss of 5-HT3A activity results in a higher density of autonomic and sensory neuronal fibers supplying bladder smooth muscle in both fetal and adult mice. Collectively, our findings highlight 5-HT3A as a critical component in the autonomic control of micturition and identify a novel role for this serotonin receptor in peripheral nervous system development.

Tethering telomeres to the inner nuclear membrane (INM) allows homologous chromosome pairing during meiosis. The meiosis-specific protein TERB1 binds the telomeric protein TRF1 to establish telomere-INM connectivity and is essential for mouse fertility. Here we solve the structure of the human TRF1-TERB1 interface to reveal the structural basis for telomere-INM linkage. Disruption of this interface abrogates binding and compromises telomere-INM attachment in mice. An embedded CDK-phosphorylation site within the TRF1-binding region of TERB1 provides a mechanism for cap exchange, a late-pachytene phenomenon involving the dissociation of the TRF1-TERB1 complex. Indeed, further strengthening this interaction interferes with cap exchange. Finally, our biochemical analysis implicates distinct complexes for telomere-INM tethering and chromosome-end protection during meiosis. Our studies unravel the structure, stoichiometry, and physiological implications underlying telomere-INM tethering, thereby providing unprecedented insights into the unique function of telomeres in meiosis.

Purpose: The aim of this study is to examine and compare with the validated, paper/pencil European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy Scale (QLQ-CIPN20), the psychometric properties of three electronically administered patient reported outcome (PRO) measures of chemotherapy-induced peripheral neuropathy (CIPN): (1) the two neuropathy items from the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), (2) the QLQ-CIPN20, and (3) the 0-10 Neuropathy Screening Question (NSQ)., Methods: We employed a descriptive, cross-sectional design and recruited 25 women with breast cancer who were receiving neurotoxic chemotherapy at an academic hospital. Participants completed the paper/pencil QLQ-CIPN20 and electronic versions of the QLQ-CIPN20, PRO-CTCAE, and NSQ. Internal consistency reliability, intraclass correlation, and concurrent and discriminant validity analyses were conducted., Results: The alpha coefficients for the electronic QLQ-CIPN20 sensory and motor subscales were 0.76 and 0.75. Comparison of the electronic and paper/pencil QLQ-CIPN20 subscales supported mode equivalence (intraclass correlation range >0.91). Participants who reported the presence of numbness/tingling via the single-item NSQ reported higher mean QLQ-CIPN20 sensory subscale scores (p < 0.001). PRO-CTCAE neuropathy severity and interference items correlated well with the QLQ-CIPN20 electronic and paper/pencil sensory (r = 0.76; r = 0.70) and motor (r = 0.55; r = 0.62) subscales, and with the NSQ (r = 0.72; r = 0.44)., Conclusion: These data support the validity of the electronically administered PRO-CTCAE neuropathy items, NSQ, and QLQ-CIPN20 for neuropathy screening in clinical practice. The electronic and paper/pencil versions of the QLQ-CIPN can be used interchangeably based on evidence of mode equivalence.

Purpose: Clinical practice guidelines on chemotherapy-induced peripheral neuropathy (CIPN) use the NCI Common Terminology Criteria for Adverse Events (CTCAE), while recent clinical trials employ a potentially superior measure, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN twenty-item scale (QLQ-CIPN20), a patient-reported outcome (PRO). Practitioners and researchers lack guidance, regarding how QLQ-CIPN20 results relate to the traditional CTCAE during the serial assessment of patients undergoing chemotherapy., Methods: Two large CIPN clinical trial datasets (538 patients) pairing QLQ-CIPN20 and CTCAE outcomes were analyzed using a multivariable linear mixed model with QLQ-CIPN20 score as the outcome variable, CTCAE grade as the main effect, and patient as random effect (accounting for internal correlation of serial measures)., Results: The association between QLQ-CIPN20 scores and CTCAE grades was strong (p < 0.0001), whereby patients with higher CTCAE grade had worse QLQ-CIPN20 scores. Some variation of QLQ-CIPN20 scores was observed based on drug, treatment, and cycle. While there was a marked difference in the mean QLQ-CIPN20 scores between CTCAE grades, the ranges of QLQ-CIPN20 scores within each CTCAE grade were large, leading to large overlap in CIPN20 scores across CTCAE grades., Conclusions: A strong positive association of QLQ-CIPN20 scores and CTCAE grade provides evidence of convergent validity as well as practical guidance, as to how to quantitatively interpret QLQ-CIPN20 scores at the study level in terms of the traditional CTCAE. The present results also highlight an important clinical caveat, specifically, that conversion of a specific QLQ-CIPN20 score to a specific CTCAE score may not be reliable at the level of an individual patient.

Background: Motor vehicle-related injuries (including off-road) are the leading cause of traumatic brain injury (TBI) and acute traumatic spinal cord injury in the United States., Objectives: To describe motocross-related head and spine injuries of adult patients presenting to an academic emergency department (ED)., Methods: We performed an observational cohort study of adult ED patients evaluated for motocross-related injuries from 2010 through 2015. Electronic health records were reviewed and data extracted using a standardized review process., Results: A total of 145 motocross-related ED visits (143 unique patients) were included. Overall, 95.2% of patients were men with a median age of 25years. Sixty-seven visits (46.2%) were associated with head or spine injuries. Forty-three visits (29.7%) were associated with head injuries, and 46 (31.7%) were associated with spine injuries. Among the 43 head injuries, 36 (83.7%) were concussions. Seven visits (16.3%) were associated with at least 1 head abnormality identified by computed tomography, including skull fracture (n=2), subdural hematoma (n=1), subarachnoid hemorrhage (n=4), intraparenchymal hemorrhage (n=3), and diffuse axonal injury (n=3). Among the 46 spine injuries, 32 (69.6%) were acute spinal fractures. Seven patients (4.9%) had clinically significant and persistent neurologic injuries. One patient (0.7%) died, and 3 patients had severe TBIs., Conclusion: Adult patients evaluated in the ED after motocross trauma had high rates of head and spine injuries with considerable morbidity and mortality. Almost half had head or spine injuries (or both), with permanent impairment for nearly 5% and death for 0.7%., (Copyright © 2017. Published by Elsevier Inc.)

The migration and fate of cranial and vagal neural crest-derived progenitor cells (NCPCs) have been extensively studied; however, much less is known about sacral NCPCs particularly in regard to their distribution in the urogenital system. To construct a spatiotemporal map of NCPC migration pathways into the developing lower urinary tract, we utilized the Sox10-H2BVenus transgene to visualize NCPCs expressing Sox10. Our aim was to define the relationship of Sox10-expressing NCPCs relative to bladder innervation, smooth muscle differentiation, and vascularization through fetal development into adulthood. Sacral NCPC migration is a highly regimented, specifically timed process, with several potential regulatory mileposts. Neuronal differentiation occurs concomitantly with sacral NCPC migration, and neuronal cell bodies are present even before the pelvic ganglia coalesce. Sacral NCPCs reside within the pelvic ganglia anlagen through 13.5 days post coitum (dpc), after which they begin streaming into the bladder body in progressive waves. Smooth muscle differentiation and vascularization of the bladder initiate prior to innervation and appear to be independent processes. In adult bladder, the majority of Sox10+ cells express the glial marker S100β, consistent with Sox10 being a glial marker in other tissues. However, rare Sox10+ NCPCs are seen in close proximity to blood vessels and not all are S100β+, suggesting either glial heterogeneity or a potential nonglial role for Sox10+ cells along vasculature. Taken together, the developmental atlas of Sox10+ NCPC migration and distribution profile of these cells in adult bladder provided here will serve as a roadmap for future investigation in mouse models of lower urinary tract dysfunction., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose/objectives: To test the content validity of a 16-item version of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy (QLQ-CIPN20). 
., Research Approach: Cross-sectional, prospective, qualitative design. 
., Setting: Six outpatient oncology clinics within the University of Michigan Health System's comprehensive cancer center in Ann Arbor. 
., Participants: 25 adults with multiple myeloma or breast, gynecologic, gastrointestinal, or head and neck malignancies experiencing peripheral neuropathy caused by neurotoxic chemotherapy. 
., Methodologic Approach: Cognitive interviewing methodology was used to evaluate the content validity of a 16-item version of the QLQ-CIPN20 instrument.
., Findings: Minor changes were made to three questions to enhance readability. Twelve questions were revised to define unfamiliar terminology, clarify the location of neuropathy, and emphasize important aspects. One question was deleted because of clinical and conceptual redundancy with other items, as well as concerns regarding generalizability and social desirability. 
., Interpretation: Cognitive interviewing methodology revealed inconsistencies between patients' understanding and researchers' intent, along with points that required clarification to avoid misunderstanding. 
., Implications for Nursing: Patients' interpretations of the instrument's items were inconsistent with the intended meanings of the questions. One item was dropped and others were revised, resulting in greater consistency in how patients, clinicians, and researchers interpreted the items' meanings and improving the instrument's content validity. Following additional revision and psychometric testing, the QLQ-CIPN20 could evolve into a gold-standard CIPN patient-reported outcome measure.

Background: People with disabilities often require assistive devices, modifications to their home environment, and physical assistance to facilitate mobility. This study examines self-reported met and unmet needs of people with disabilities who use wheeled mobility devices, compared with non-users., Data and Methods: The 2012 Canadian Survey on Disability followed up with 45,442 individuals who reported a disability on the 2011 National Household Survey, and obtained a 75% response rate. Descriptive statistics with variance estimates and 95% confidence intervals were used to compare wheeled mobility device users and non-users., Results: Nearly 10% of wheeled mobility device users identified an unmet need for an additional mobility device. Compared with non-users, they were twice as likely to modify their home with a ramp and three times as likely to install a lift. The prevalence of unmet need for each type of residence adaptation among wheeled mobility device users was at least double that of non-users. Wheeled mobility device users received assistance with an average of 4.4 activities, compared with 2.0 for non-users, and reported an average of 1.9 activities for which assistance was needed but not received. About one in three relied on paid assistance; for 14% of those who paid for assistance, out-of-pocket expenses amounted to $10,000 or more annually, compared with 2% among non-users., Interpretation: Wheeled mobility device users reported a higher prevalence of met and unmet needs for residence modifications than did non-users. They required help with more activities of life on a more frequent basis, with greater dependence on paid individuals, resulting in higher out-of-pocket expenses. Power and manual wheelchair users reported greater needs than did mobility scooter users.