• Uncovering genomic regions associated with trypanosoma infections in wild populations of the tsetse fly Glossina fuscipes

      Gloria-Soria, A; Augustine Dunn, W; Yu, X; Vigneron, A; Lee, KY; Li, M; Weiss, BL; Zhao, H; Aksoy, S; Caccone, A (2018-03-01)
      © 2018 Andrea et al. Vector-borne diseases are responsible for > 1 million deaths every year but genomic resources for most species responsible for their transmission are limited. This is true for neglected diseases such as sleeping sickness (Human African Trypanosomiasis), a disease caused by Trypanosoma parasites vectored by several species of tseste flies within the genus Glossina. We describe an integrative approach that identifies statistical associations between trypanosome infection status of Glossina fuscipes fuscipes (Gff ) flies from Uganda, for which functional studies are complicated because the species cannot be easily maintained in laboratory colonies, and ~73,000 polymorphic sites distributed across the genome. Then, we identify candidate genes involved in Gff trypanosome susceptibility by taking advantage of genomic resources from a closely related species, G. morsitans morsitans (Gmm). We compiled a comprehensive transcript library from 72 published and unpublished RNAseq experiments of trypanosome-infected and uninfected Gmm flies, and improved the current Gmm transcriptome assembly. This new assembly was then used to enhance the functional annotations on the Gff genome. As a consequence, we identified 56 candidate genes in the vicinity of the 18 regions associated with Trypanosoma infection status in Gff. Twenty-nine of these genes were differentially expressed (DE) among parasite-infected and uninfected Gmm, suggesting that their orthologs in Gff may correlate with disease transmission. These genes were involved in DNA regulation, neurophysiological functions, and immune responses. We highlight the power of integrating population and functional genomics from related species to enhance our understanding of the genetic basis of physiological traits, particularly in nonmodel organisms.
    • Under the Canopy: Migration Governance in Southeast Asia

      Ramji-Nogales, Jaya (2017)
      Contrary to prevailing discourse, migration governance in Southeast Asia is rich and varied, offering a range of regional, bilateral and subnational regimes. Many commentators characterize Southeast Asia as lacking adequate migration governance, and media reports highlight human rights abuses against migrants in the region. These depictions offer only partial truths, overlooking the complexity of law and practice in the region. Though few Southeast Asian nations are signatories to the United Nations Convention Relating to the Status of Refugees, many have ratified other multilateral international treaties relating to migration. Looking deeper under the canopy, this article explores the full panoply of migration regimes, noting not only gaps in governance frameworks but also creative approaches, some of which may provide models for other regions. While many migrants in the region suffer serious harms, others benefit from innovative and generous migration policies. These regional, bilateral, and subnational approaches are often more deeply grounded in local value systems than international treaties. As a result, local populations may accord greater legitimacy to these under-the-canopy approaches, which may in the long run be more effective in improving the situation of migrants in Southeast Asia. The view from above the canopy is blocked by a sea of green leaves; one must take the time to peer under the canopy in order to gain an accurate understanding of migration governance in Southeast Asia.
    • Understanding help-seeking intentions in male military cadets: An application of perceptual mapping

      Bass, SB; Muñiz, J; Gordon, TF; Maurer, L; Patterson, F (2016-05-17)
      © 2016 Bass et al. Background: Research suggests that men are less likely to seek help for depression, substance abuse, and stressful life events due to negative perceptions of asking for and receiving help. This may be exacerbated in male military cadets who exhibit higher levels of gender role conflict because of military culture. Methods: This exploratory study examined the perceptions of 78 male military cadets toward help-seeking behaviors. Cadets completed the 31-item Barriers to Help Seeking Scale (BHSS) and a component factor analysis was used to generate five composite variables and compare to validated factors. Perceptual mapping and vector modeling, which produce 3-dimensional models of a group's perceptions, were then used to model how they conceptualize help-seeking. Results: Factor analysis showed slightly different groupings than the BHSS, perhaps attributed to different characteristics of respondents, who are situated in a military school compared to general university males. Perceptual maps show that cadets perceive trust of doctors closest to them and help-seeking farthest, supporting the concept that these males have rigid beliefs about having control and its relationship to health seeking. Differences were seen when comparing maps of White and non-White cadets. White cadets positioned themselves far away from all variables, while non-White cadets were closest to "emotional control". Conclusion: To move these cadets toward help-seeking, vector modeling suggests that interventions should focus on their general trust of doctors, accepting lack of control, and decreasing feelings of weakness when asking for help. For non-White cadets a focus on self-reliance may also need to be emphasized. Use of these unique methods resulted in articulation of specific barriers that if addressed early, may have lasting effects on help-seeking behavior as these young men become adults. Future studies are needed to develop and test specific interventions to promote help-seeking among military cadets.
    • Understanding Holistic Graduate Admissions Practices: Summary of a Current Research Study

      Paris, Joseph; 0000-0001-7636-903X (2021)
      Holistic review, or the consideration of a wide range of applicant qualities including “non-cognitive” or personal attributes, is a growing strategy for expanding the predictive potential derived from the variables most commonly evaluated in graduate admissions: cumulative undergraduate GPA and standardized test scores such as the GRE (Kent & McCarthy, 2016; Okahana et al., 2018). This article describes a NAGAP-sponsored research study that responds to the need identified by Kent and McCarthy (2016) for a “clearer understanding of what constitutes a truly ‘holistic’ graduate admissions process for master’s and doctoral programs” (p. iv). The project also aims to generate guidelines for the practice of holistic review in graduate admissions.
    • Undocumented Migrants and the Failures of Universal Individualism

      Ramji-Nogales, Jaya (2014-05)
      In recent years, advocates and scholars have made increasing efforts to situate undocumented migrants within the human rights framework. Few have examined international human rights law closely enough to discover just how limited it is in its protections of the undocumented. This Article takes that failure as a starting point to launch a critique of the universal individualist project that characterizes the current human rights system. It then catalogues in detail the protections available to undocumented migrants in international human rights law, which are far fewer than often assumed. The Article demonstrates through a close analysis of relevant law that the human rights framework contains significant conceptual gaps when it comes to the undocumented. It concludes by suggesting three alternate approaches — substantial reform of the current human rights system state-based political responses, and social movements — to protect undocumented migrants and other vulnerable populations.
    • Unfoldomics of human diseases: Linking protein intrinsic disorder with diseases

      Uversky, VN; Oldfield, CJ; Midic, U; Xie, H; Xue, B; Vucetic, S; Iakoucheva, LM; Obradovic, Z; Keith, AK (2009-07-07)
      Background: Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) lack stable tertiary and/or secondary structure yet fulfills key biological functions. The recent recognition of IDPs and IDRs is leading to an entire field aimed at their systematic structural characterization and at determination of their mechanisms of action. Bioinformatics studies showed that IDPs and IDRs are highly abundant in different proteomes and carry out mostly regulatory functions related to molecular recognition and signal transduction. These activities complement the functions of structured proteins. IDPs and IDRs were shown to participate in both one-to-many and many-to-one signaling. Alternative splicing and posttranslational modifications are frequently used to tune the IDP functionality. Several individual IDPs were shown to be associated with human diseases, such as cancer, cardiovascular disease, amyloidoses, diabetes, neurodegenerative diseases, and others. This raises questions regarding the involvement of IDPs and IDRs in various diseases. Results: IDPs and IDRs were shown to be highly abundant in proteins associated with various human maladies. As the number of IDPs related to various diseases was found to be very large, the concepts of the disease-related unfoldome and unfoldomics were introduced. Novel bioinformatics tools were proposed to populate and characterize the disease-associated unfoldome. Structural characterization of the members of the disease-related unfoldome requires specialized experimental approaches. IDPs possess a number of unique structural and functional features that determine their broad involvement into the pathogenesis of various diseases. Conclusion: Proteins associated with various human diseases are enriched in intrinsic disorder. These disease-associated IDPs and IDRs are real, abundant, diversified, vital, and dynamic. These proteins and regions comprise the disease-related unfoldome, which covers a significant part of the human proteome. Profound association between intrinsic disorder and various human diseases is determined by a set of unique structural and functional characteristics of IDPs and IDRs. Unfoldomics of human diseases utilizes unrivaled bioinformatics and experimental techniques, paves the road for better understanding of human diseases, their pathogenesis and molecular mechanisms, and helps develop new strategies for the analysis of disease-related proteins. © 2009 Uversky et al; licensee BioMed Central Ltd.
    • Universality and chaoticity in ultracold K+KRb chemical reactions

      Croft, JFE; Makrides, C; Li, M; Petrov, A; Kendrick, BK; Balakrishnan, N; Kotochigova, S; Li, Ming|0000-0003-0827-5976 (2017-07-19)
      © The Author(s) 2017. A fundamental question in the study of chemical reactions is how reactions proceed at a collision energy close to absolute zero. This question is no longer hypothetical: quantum degenerate gases of atoms and molecules can now be created at temperatures lower than a few tens of nanokelvin. Here we consider the benchmark ultracold reaction between, the most-celebrated ultracold molecule, KRb and K. We map out an accurate ab initio ground-state potential energy surface of the K2Rb complex in full dimensionality and report numerically-exact quantum-mechanical reaction dynamics. The distribution of rotationally resolved rates is shown to be Poissonian. An analysis of the hyperspherical adiabatic potential curves explains this statistical character revealing a chaotic distribution for the short-range collision complex that plays a key role in governing the reaction outcome.
    • Unproductive effects of alk gene amplification and copy number gain in non-small-cell lung cancer. Alk gene amplification and copy gain in nsclc

      Marino, FZ; Botti, G; Aquino, G; Ferrero, S; Gaudioso, G; Palleschi, A; Rocco, D; Salvi, R; Micheli, MC; Micheli, P; Morabito, A; Rocco, G; Giordano, A; De Cecio, R; Franco, R; Giordano, Antonio|0000-0002-5959-016X (2020-07-02)
      © 2020 by the authors. Licensee MDPI, Basel, Switzerland. Background: The Anaplastic Lymphoma Kinase (ALK) gene is known to be affected by several genetic alterations, such as rearrangement, amplification and point mutation. The main goal of this study was to comprehensively analyze ALK amplification (ALK-A) and ALK gene copy number gain (ALK-CNG) in a large cohort of non-small-cell lung cancer (NSCLC) patients in order to evaluate the effects on mRNA and protein expression. Methods: ALK locus number status was evaluated in 578 NSCLC cases by fluorescence in situ hybridization (FISH). In addition, ALK immunohistochemistry and ALK mRNA in situ hybridization were performed. Results: Out of 578 cases, 17 cases showed ALK-A. In addition, 14 cases presented ALK-CNG and 72 cases presented chromosome 2 polyploidy. None of those carrying ALK-A and-CNG showed either ALK immunohistochemical expression or ALK mRNA expression through in situ hybridization. We observed a high frequency of extra copies of the ALK gene. Conclusions: Our findings demonstrated that ALK-A is not involved in mRNA production and consequently is not involved in protein production; these findings support the hypothesis that ALK-A might not play a role in the pathogenesis of NSCLC, underlining the absence of a specific clinical application.
    • Unsupervised Integration of Multiple Protein Disorder Predictors: The Method and Evaluation on CASP7, CASP8 and CASP9 Data

      Zhang, P; Obradovic, Z (2011-10-14)
      Background: Studies of intrinsically disordered proteins that lack a stable tertiary structure but still have important biological functions critically rely on computational methods that predict this property based on sequence information. Although a number of fairly successful models for prediction of protein disorder have been developed over the last decade, the quality of their predictions is limited by available cases of confirmed disorders.Results: To more reliably estimate protein disorder from protein sequences, an iterative algorithm is proposed that integrates predictions of multiple disorder models without relying on any protein sequences with confirmed disorder annotation. The iterative method alternately provides the maximum a posterior (MAP) estimation of disorder prediction and the maximum-likelihood (ML) estimation of quality of multiple disorder predictors. Experiments on data used at CASP7, CASP8, and CASP9 have shown the effectiveness of the proposed algorithm.Conclusions: The proposed algorithm can potentially be used to predict protein disorder and provide helpful suggestions on choosing suitable disorder predictors for unknown protein sequences. © 2011 Zhang and Obradovic; licensee BioMed Central Ltd.
    • Upper limb rehabilitation in chronic stroke using neurologic music therapy: Two contrasting case studies to inform on treatment delivery and patient suitability

      Street, Alexander J.; Ruskin, Anglia; Fachner, Jörg; Magee, Wendy L.; Magee|0000-0003-4350-1289 (2019-05-14)
      Introduction: Therapeutic Instrumental Music Performance (TIMP) is well suited for upper limb rehabilitation following stroke. Published protocols serve to inform clinicians on intervention design and delivery. However, few case studies are available that address patient suitability, protocol modifications to support treatment adherence and suitability of home environment. Methods: Two case studies from a small randomized controlled trial illustrate TIMP protocol modifications and considerations required for home delivery. Qualitative, quantitative and observational data report on participants‘ outcomes and engagement with six weeks of bi-weekly exercises. TIMP adaptations to enhance audio-motor synchronization are described. Results: Outcomes for the less impaired participant with fewer complex health needs were significantly better after six weeks, particularly pinch grip (1 peg in 20 seconds to 15/120). The second participant improved on the water pouring task: 44 seconds to 13.16. Discussion: Severity of stroke and impairment are major factors influencing treatment outcomes. Flexibility in the TIMP protocols, such as emphasizing the underlying pulse and building the dynamic contour, aids treatment adherence and movement synchrony. It is essential to assess homes for access, sound containment and space. Outcome measures for detecting compensatory movement, smoothness and velocity of movement are needed to better inform treatment effects.
    • Upregulation of hsa_circ_0007874 suppresses the progression of ovarian cancer by regulating the miR-760/SOCS3 pathway

      Li, L; Yu, P; Zhang, P; Wu, H; Chen, Q; Li, S; Wang, Y; Wu, Huanmei|0000-0003-0346-6044 (2020-04-01)
      © 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. Ovarian cancer (OVA) is a fatal and common malignancy in women worldwide. Circular RNAs (circRNAs) consist of a family of circular endogenous RNAs generated by selective splicing, and they are involved in many diseases. Previous studies reported that hsa_circ_0007874 is aberrantly expressed in cancer and functions in tumorigenesis. While the hsa_circ_0007874 role in OVA is unclear. Here, we detected the hsa_circ_0007874 expression in OVA cell lines using Rt-qPCR. Hsa_circ_0007874 subcellular localization was confirmed by fluorescence in situ hybridization. The relationship between hsa_circ_0007874, microRNAs (miRNAs), and relative protein levels was assessed using the luciferase reporter assays. Results verified that hsa_circ_0007874 is downregulated in OVA cell lines. hsa_circ_0007874 overexpression decreased the OVA cell migration and proliferation in vitro and in vivo. Bioinformatics and luciferase reporter assays confirmed that miR-760 and SOCS3 are the downstream targets of hsa_circ_0007874. Downregulation of SOCS3 or miR-760 overexpression restored the migration and proliferation ability of SKOV3 or A2780 cells overexpressing hsa_circ_0007874. Downregulation of SOCS3 restored the proliferation and migration in miR-760 knockdown SKOV3 and A2780 cells. In summary, the data suggest that hsa_circ_0007874 acts as a tumor suppressor by regulating the miR-760/SOCS3 axis, highlighting its potential as an effective therapeutic target for OVA.
    • Use of attribute association error probability estimates to evaluate quality of medical record geocodes

      Klaus, CA; Carrasco, LE; Goldberg, DW; Henry, KA; Sherman, RL (2015-09-15)
      © 2015 Klaus et al. Background: The utility of patient attributes associated with the spatiotemporal analysis of medical records lies not just in their values but also the strength of association between them. Estimating the extent to which a hierarchy of conditional probability exists between patient attribute associations such as patient identifying fields, patient and date of diagnosis, and patient and address at diagnosis is fundamental to estimating the strength of association between patient and geocode, and patient and enumeration area. We propose a hierarchy for the attribute associations within medical records that enable spatiotemporal relationships. We also present a set of metrics that store attribute association error probability (AAEP), to estimate error probability for all attribute associations upon which certainty in a patient geocode depends. Methods: A series of experiments were undertaken to understand how error estimation could be operationalized within health data and what levels of AAEP in real data reveal themselves using these methods. Specifically, the goals of this evaluation were to (1) assess if the concept of our error assessment techniques could be implemented by a population-based cancer registry; (2) apply the techniques to real data from a large health data agency and characterize the observed levels of AAEP; and (3) demonstrate how detected AAEP might impact spatiotemporal health research. Results: We present an evaluation of AAEP metrics generated for cancer cases in a North Carolina county. We show examples of how we estimated AAEP for selected attribute associations and circumstances. We demonstrate the distribution of AAEP in our case sample across attribute associations, and demonstrate ways in which disease registry specific operations influence the prevalence of AAEP estimates for specific attribute associations. Conclusions: The effort to detect and store estimates of AAEP is worthwhile because of the increase in confidence fostered by the attribute association level approach to the assessment of uncertainty in patient geocodes, relative to existing geocoding related uncertainty metrics.
    • Use of quantitative molecular diagnostic methods to assess the aetiology, burden, and clinical characteristics of diarrhoea in children in low-resource settings: a reanalysis of the MAL-ED cohort study

      Platts-Mills, JA; Liu, J; Rogawski, ET; Kabir, F; Lertsethtakarn, P; Siguas, M; Khan, SS; Praharaj, I; Murei, A; Nshama, R; Mujaga, B; Havt, A; Maciel, IA; McMurry, TL; Operario, DJ; Taniuchi, M; Gratz, J; Stroup, SE; Roberts, JH; Kalam, A; Aziz, F; Qureshi, S; Islam, MO; Sakpaisal, P; Silapong, S; Yori, PP; Rajendiran, R; Benny, B; McGrath, M; McCormick, BJJ; Seidman, JC; Lang, D; Gottlieb, M; Guerrant, RL; Lima, AAM; Leite, JP; Samie, A; Bessong, PO; Page, N; Bodhidatta, L; Mason, C; Shrestha, S; Kiwelu, I; Mduma, ER; Iqbal, NT; Bhutta, ZA; Ahmed, T; Haque, R; Kang, G; Kosek, MN; Houpt, ER; Acosta, AM; Rios de Burga, R; Chavez, CB; Flores, JT; Olotegui, MP; Pinedo, SR; Trigoso, DR; Vasquez, AO; Ahmed, I; Alam, D; Ali, A; Rasheed, M; Soofi, S; Turab, A; Yousafzai, A; Zaidi, AK; Shrestha, B; Rayamajhi, BB; Strand, T; Ammu, G; Babji, S; Bose, A; George, AT; Hariraju, D; Jennifer, MS; John, S; Kaki, S; Karunakaran, P; Koshy, B; Lazarus, RP; Muliyil, J; Ragasudha, P; Raghava, MV; Raju, S; Ramachandran, A; Ramadas, R; Ramanujam, K; Rose, A; Roshan, R; Sharma, SL; Sundaram, S; Thomas, RJ; Pan, WK; Ambikapathi, R; Carreon, JD; Doan, V; Hoest, C; Knobler, S; Miller, MA (2018-12-01)
      © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Optimum management of childhood diarrhoea in low-resource settings has been hampered by insufficient data on aetiology, burden, and associated clinical characteristics. We used quantitative diagnostic methods to reassess and refine estimates of diarrhoea aetiology from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study. Methods: We re-analysed stool specimens from the multisite MAL-ED cohort study of children aged 0–2 years done at eight locations (Dhaka, Bangladesh; Vellore, India; Bhaktapur, Nepal; Naushero Feroze, Pakistan; Venda, South Africa; Haydom, Tanzania; Fortaleza, Brazil; and Loreto, Peru), which included active surveillance for diarrhoea and routine non-diarrhoeal stool collection. We used quantitative PCR to test for 29 enteropathogens, calculated population-level pathogen-specific attributable burdens, derived stringent quantitative cutoffs to identify aetiology for individual episodes, and created aetiology prediction scores using clinical characteristics. Findings: We analysed 6625 diarrhoeal and 30 968 non-diarrhoeal surveillance stools from 1715 children. Overall, 64·9% of diarrhoea episodes (95% CI 62·6–71·2) could be attributed to an aetiology by quantitative PCR compared with 32·8% (30·8–38·7) using the original study microbiology. Viral diarrhoea (36·4% of overall incidence, 95% CI 33·6–39·5) was more common than bacterial (25·0%, 23·4–28·4) and parasitic diarrhoea (3·5%, 3·0–5·2). Ten pathogens accounted for 95·7% of attributable diarrhoea: Shigella (26·1 attributable episodes per 100 child-years, 95% CI 23·8–29·9), sapovirus (22·8, 18·9–27·5), rotavirus (20·7, 18·8–23·0), adenovirus 40/41 (19·0, 16·8–23·0), enterotoxigenic Escherichia coli (18·8, 16·5–23·8), norovirus (15·4, 13·5–20·1), astrovirus (15·0, 12·0–19·5), Campylobacter jejuni or C coli (12·1, 8·5–17·2), Cryptosporidium (5·8, 4·3–8·3), and typical enteropathogenic E coli (5·4, 2·8–9·3). 86·2% of the attributable incidence for Shigella was non-dysenteric. A prediction score for shigellosis was more accurate (sensitivity 50·4% [95% CI 46·7–54·1], specificity 84·0% [83·0–84·9]) than current guidelines, which recommend treatment only of bloody diarrhoea to cover Shigella (sensitivity 14·5% [95% CI 12·1–17·3], specificity 96·5% [96·0–97·0]). Interpretation: Quantitative molecular diagnostics improved estimates of pathogen-specific burdens of childhood diarrhoea in the community setting. Viral causes predominated, including a substantial burden of sapovirus; however, Shigella had the highest overall burden with a high incidence in the second year of life. These data could improve the management of diarrhoea in these low-resource settings. Funding: Bill & Melinda Gates Foundation.
    • Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study

      Rogawski, ET; Liu, J; Platts-Mills, JA; Kabir, F; Lertsethtakarn, P; Siguas, M; Khan, SS; Praharaj, I; Murei, A; Nshama, R; Mujaga, B; Havt, A; Maciel, IA; Operario, DJ; Taniuchi, M; Gratz, J; Stroup, SE; Roberts, JH; Kalam, A; Aziz, F; Qureshi, S; Islam, MO; Sakpaisal, P; Silapong, S; Yori, PP; Rajendiran, R; Benny, B; McGrath, M; Seidman, JC; Lang, D; Gottlieb, M; Guerrant, RL; Lima, AAM; Leite, JP; Samie, A; Bessong, PO; Page, N; Bodhidatta, L; Mason, C; Shrestha, S; Kiwelu, I; Mduma, ER; Iqbal, NT; Bhutta, ZA; Ahmed, T; Haque, R; Kang, G; Kosek, MN; Houpt, ER; Acosta, AM; Rios de Burga, R; Chavez, CB; Flores, JT; Olotegui, MP; Pinedo, SR; Trigoso, DR; Vasquez, AO; Ahmed, I; Alam, D; Ali, A; Rasheed, M; Soofi, S; Turab, A; Yousafzai, A; Zaidi, AK; Shrestha, B; Rayamajhi, BB; Strand, T; Ammu, G; Babji, S; Bose, A; George, AT; Hariraju, D; Jennifer, MS; John, S; Kaki, S; Karunakaran, P; Koshy, B; Lazarus, RP; Muliyil, J; Ragasudha, P; Raghava, MV; Raju, S; Ramachandran, A; Ramadas, R; Ramanujam, K; Rose, A; Roshan, R; Sharma, SL; Sundaram, S; Thomas, RJ; Pan, WK; Ambikapathi, R; Carreon, JD; Doan, V; Hoest, C; Knobler, S; McCormick, BJ; Miller, MA; Psaki, S (2018-12-01)
      © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Enteropathogen infections in early childhood not only cause diarrhoea but contribute to poor growth. We used molecular diagnostics to assess whether particular enteropathogens were associated with linear growth across seven low-resource settings. Methods: We used quantitative PCR to detect 29 enteropathogens in diarrhoeal and non-diarrhoeal stools collected from children in the first 2 years of life obtained during the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) multisite cohort study. Length was measured monthly. We estimated associations between aetiology-specific diarrhoea and subclinical enteropathogen infection and quantity and attained length in 3 month intervals, at age 2 and 5 years, and used a longitudinal model to account for temporality and time-dependent confounding. Findings: Among 1469 children who completed 2 year follow-up, 35 622 stool samples were tested and yielded valid results. Diarrhoeal episodes attributed to bacteria and parasites, but not viruses, were associated with small decreases in length after 3 months and at age 2 years. Substantial decrements in length at 2 years were associated with subclinical, non-diarrhoeal, infection with Shigella (length-for-age Z score [LAZ] reduction −0·14, 95% CI −0·27 to −0·01), enteroaggregative Escherichia coli (−0·21, −0·37 to −0·05), Campylobacter (−0·17, −0·32 to −0·01), and Giardia (−0·17, −0·30 to −0·05). Norovirus, Cryptosporidium, typical enteropathogenic E coli, and Enterocytozoon bieneusi were also associated with small decrements in LAZ. Shigella and E bieneusi were associated with the largest decreases in LAZ per log increase in quantity per g of stool (−0·13 LAZ, 95% CI −0·22 to −0·03 for Shigella; −0·14, −0·26 to −0·02 for E bieneusi). Based on these models, interventions that successfully decrease exposure to Shigella, enteroaggregative E coli, Campylobacter, and Giardia could increase mean length of children by 0·12–0·37 LAZ (0·4–1·2 cm) at the MAL-ED sites. Interpretation: Subclinical infection and quantity of pathogens, particularly Shigella, enteroaggregative E coli, Campylobacter, and Giardia, had a substantial negative association with linear growth, which was sustained during the first 2 years of life, and in some cases, to 5 years. Successfully reducing exposure to certain pathogens might reduce global stunting. Funding: Bill & Melinda Gates Foundation.
    • Using analogy to learn about phenomena at scales outside human perception

      Resnick, I; Davatzes, A; Newcombe, NS; Shipley, TF (2017-12-01)
      © 2017, The Author(s). Understanding and reasoning about phenomena at scales outside human perception (for example, geologic time) is critical across science, technology, engineering, and mathematics. Thus, devising strong methods to support acquisition of reasoning at such scales is an important goal in science, technology, engineering, and mathematics education. In two experiments, we examine the use of analogical principles in learning about geologic time. Across both experiments we find that using a spatial analogy (for example, a time line) to make multiple alignments, and keeping all unrelated components of the analogy held constant (for example, keep the time line the same length), leads to better understanding of the magnitude of geologic time. Effective approaches also include hierarchically and progressively aligning scale information (Experiment 1) and active prediction in making alignments paired with immediate feedback (Experiments 1 and 2).
    • Using Best–Worst Scaling to Investigate Preferences in Health Care

      Cheung, KL; Wijnen, BFM; Hollin, IL; Janssen, EM; Bridges, JF; Evers, SMAA; Hiligsmann, M (2016-12-01)
      © 2016, The Author(s). Introduction: Best–worst scaling (BWS) is becoming increasingly popular to elicit preferences in health care. However, little is known about current practice and trends in the use of BWS in health care. This study aimed to identify, review and critically appraise BWS in health care, and to identify trends over time in key aspects of BWS. Methods: A systematic review was conducted, using Medline (via Pubmed) and EMBASE to identify all English-language BWS studies published up until April 2016. Using a predefined extraction form, two reviewers independently selected articles and critically appraised the study quality, using the Purpose, Respondents, Explanation, Findings, Significance (PREFS) checklist. Trends over time periods (≤2010, 2011, 2012, 2013, 2014 and 2015) were assessed further. Results: A total of 62 BWS studies were identified, of which 26 were BWS object case studies, 29 were BWS profile case studies and seven were BWS multi-profile case studies. About two thirds of the studies were performed in the last 2 years. Decreasing sample sizes and decreasing numbers of factors in BWS object case studies, as well as use of less complicated analytical methods, were observed in recent studies. The quality of the BWS studies was generally acceptable according to the PREFS checklist, except that most studies did not indicate whether the responders were similar to the non-responders. Conclusion: Use of BWS object case and BWS profile case has drastically increased in health care, especially in the last 2 years. In contrast with previous discrete-choice experiment reviews, there is increasing use of less sophisticated analytical methods.
    • Using comparative genomic hybridization to survey genomic sequence divergence across species: A proof-of-concept from Drosophila

      Renn, SCP; Machado, HE; Jones, A; Soneji, K; Kulathinal, RJ; Hofmann, HA; Kulathinal, Rob|0000-0003-1907-2744 (2010-04-29)
      Background: Genome-wide analysis of sequence divergence among species offers profound insights into the evolutionary processes that shape lineages. When full-genome sequencing is not feasible for a broad comparative study, we propose the use of array-based comparative genomic hybridization (aCGH) in order to identify orthologous genes with high sequence divergence. Here we discuss experimental design, statistical power, success rate, sources of variation and potential confounding factors. We used a spotted PCR product microarray platform from Drosophila melanogaster to assess sequence divergence on a gene-by-gene basis in three fully sequenced heterologous species (D. sechellia, D. simulans, and D. yakuba). Because complete genome assemblies are available for these species this study presents a powerful test for the use of aCGH as a tool to measure sequence divergence.Results: We found a consistent and linear relationship between hybridization ratio and sequence divergence of the sample to the platform species. At higher levels of sequence divergence (< 92% sequence identity to D. melanogaster) ~84% of features had significantly less hybridization to the array in the heterologous species than the platform species, and thus could be identified as "diverged". At lower levels of divergence (≥ 97% identity), only 13% of genes were identified as diverged. While ~40% of the variation in hybridization ratio can be accounted for by variation in sequence identity of the heterologous sample relative to D. melanogaster, other individual characteristics of the DNA sequences, such as GC content, also contribute to variation in hybridization ratio, as does technical variation.Conclusions: Here we demonstrate that aCGH can accurately be used as a proxy to estimate genome-wide divergence, thus providing an efficient way to evaluate how evolutionary processes and genomic architecture can shape species diversity in non-model systems. Given the increased number of species for which microarray platforms are available, comparative studies can be conducted for many interesting lineages in order to identify highly diverged genes that may be the target of natural selection. © 2010 Renn et al; licensee BioMed Central Ltd.
    • Using disease-associated coding sequence variation to investigate functional compensation by human paralogous proteins

      Miura, S; Tate, S; Kumar, S; Kumar, Sudhir|0000-0002-9918-8212 (2015-11-02)
      © the authors, publisher and licensee Libertas Academica Limited. Gene duplication enables the functional diversification in species. It is thought that duplicated genes may be able to compensate if the function of one of the gene copies is disrupted. This possibility is extensively debated with some studies reporting proteome-wide compensation, whereas others suggest functional compensation among only recent gene duplicates or no compensation at all. We report results from a systematic molecular evo-lutionary analysis to test the predictions of the functional compensation hypothesis. We contrasted the density of Mendelian disease-associated single nucleotide variants (dSNVs) in proteins with no discernable paralogs (singletons) with the dSNV density in proteins found in multigene families. Under the functional compensation hypothesis, we expected to find greater numbers of dSNVs in singletons due to the lack of any compensating partners. Our analy-ses produced an opposite pattern; paralogs have over 35% higher dSNV density than singletons. We found that these patterns are concordant with similar differences in the rates of amino acid evolution (ie, functional constraints), as the proteins with paralogs have evolved 33% slower than singletons. Our evolutionary constraint explanation is robust to differences in family sizes, ages (young vs. old duplicates), and degrees of amino acid sequence similarities among paralogs. Therefore, disease-associated human variation does not exhibit significant signals of functional compensation among paralogous proteins, but rather an evolutionary constraint hypothesis provides a better explanation for the observed patterns of disease-associated and neutral polymorphisms in the human genome.
    • Using eye tracking and gaze pattern analysis to test a "dirty bomb" decision aid in a pilot RCT in urban adults with limited literacy

      Bass, SB; Gordon, TF; Gordon, R; Parvanta, C (2016-06-08)
      © 2016 The Author(s). Background: Eye tracking is commonly used in marketing to understand complex responses to materials, but has not been used to understand how low-literacy adults access health information or its relationship to decision making. Methods: This study assessed how participants use a literacy appropriate "dirty bomb" decision aid. Participants were randomized to receive a CDC "factsheet" (n = 21) or literacy-appropriate aid (n = 29) shown on a computer screen. Using 7 content similar slides, gaze patterns, mean pupil fixation time and mean overall time reading and looking at slides were compared. Groups were also compared by literacy level and effect on 'confidence of knowledge' and intended behavior. Results: Results revealed differing abilities to read densely written material. Intervention participants more precisely followed text on 4 of 7 content-similar slides compared to control participants whose gaze patterns indicated unread text, or repeated attempts at reading the same text, suggesting difficulty in understanding key preparedness messages. Controls had significantly longer pupil fixations on 5 of 7 slides and spent more overall time on every slide. In those with very low literacy, intervention participants were more likely than controls to say they understood what a "dirty bomb" is and how to respond if one should occur. Conclusions: Results indicate limited- literacy adults, especially those with very low literacy, may not be able to understand how to respond during a "dirty bomb" using available materials, making them vulnerable to negative health events. This study provides insights into how individuals perceive and process risk communication messages, illustrating a rich and nuanced understanding of the qualitative experience of a limited literacy population with written materials. It also demonstrates the feasibility of using these methods on a wider scale to develop more effective health and risk communication messages designed to increase knowledge of and compliance with general health guidelines, and enhance decision making. This has application for those with learning disabilities, those with limited media-literacy skills, and those needing to access the diverse array of assistive technologies now available. Eye tracking is thus a practical approach to understanding these diverse needs to ensure the development of cogent and salient communication.
    • Using HIV Transmission Networks to Investigate Community Effects in HIV Prevention Trials

      Wertheim, JO; Kosakovsky Pond, SL; Little, SJ; De Gruttola, V; Pond, Sergei L. Kosakovsky|0000-0003-4817-4029 (2011-12-01)
      Effective population screening of HIV and prevention of HIV transmission are only part of the global fight against AIDS. Community-level effects, for example those aimed at thwarting future transmission, are potential outcomes of treatment and may be important in stemming the epidemic. However, current clinical trial designs are incapable of detecting a reduction in future transmission due to treatment. We took advantage of the fact that HIV is an evolving pathogen whose transmission network can be reconstructed using genetic sequence information to address this shortcoming. Here, we use an HIV transmission network inferred from recently infected men who have sex with men (MSM) in San Diego, California. We developed and tested a network-based statistic for measuring treatment effects using simulated clinical trials on our inferred transmission network. We explored the statistical power of this network-based statistic against conventional efficacy measures and find that when future transmission is reduced, the potential for increased statistical power can be realized. Furthermore, our simulations demonstrate that the network statistic is able to detect community-level effects (e.g., reduction in onward transmission) of HIV treatment in a clinical trial setting. This study demonstrates the potential utility of a network-based statistical metric when investigating HIV treatment options as a method to reduce onward transmission in a clinical trial setting. © 2011 Wertheim et al.