bluuebunny/crossref_metadata_2025 huggingface dataset:
Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers
Authors: Kachuri Linda , Saarela Olli , Bojesen Stig Egil , Davey Smith George , Liu Geoffrey , Landi Maria Teresa , Caporaso Neil E , Christiani David C , Johansson Mattias , Panico Salvatore , Overvad Kim , Trichopoulou Antonia , Vineis Paolo , Scelo Ghislaine , Zaridze David , Wu Xifeng , Albanes Demetrius , Diergaarde Brenda , Lagiou Pagona , Macfarlane Gary J , Aldrich Melinda C , Tardón Adonina , Rennert Gad , Olshan Andrew F , Weissler Mark C , Chen Chu , Goodman Gary E , Doherty Jennifer A , Ness Andrew R , Bickeböller Heike , Wichmann H-Erich , Risch Angela , Field John K , Teare M Dawn , Kiemeney Lambertus A , van der Heijden Erik H F M , Carroll June C , Haugen Aage , Zienolddiny Shanbeh , Skaug Vidar , Wünsch-Filho Victor , Tajara Eloiza H , Ayoub Moysés Raquel , Daumas Nunes Fabio , Lam Stephen , Eluf-Neto Jose , Lacko Martin , Peters Wilbert H M , Le Marchand Loïc , Duell Eric J , Andrew Angeline S , Franceschi Silvia , Schabath Matthew B , Manjer Jonas , Arnold Susanne , Lazarus Philip , Mukeriya Anush , Swiatkowska Beata , Janout Vladimir , Holcatova Ivana , Stojsic Jelena , Mates Dana , Lissowska Jolanta , Boccia Stefania , Lesseur Corina , Zong Xuchen , McKay James D , Brennan Paul , Amos Christopher I , Hung Rayjean J
Published: June 2018

Background

Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses.

Methods

We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects.

Results

The multi-allelic 5p15.33 instrument explained 1.49–2.00% of TL variation in our data (p = 2.6 × 10–9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20–1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51–2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83–1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70–1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95–1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk.

Conclusions

Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.
Post-streptococcal glomerulonephritis
Authors: Rodríguez-Iturbe Bernardo , Haas Mark
Published: June 2018

Post-streptococcal glomerulonephritis is a complication of Streptococcal infections that is responsible for classic acute nephritic syndrome, mostly seen in children. This is an acute nephritis associated with prominent fluid retention and oedema, hypertension and haematuria. Serum complement levels are diagnostically helpful as C3 levels are characteristically very low. However, many cases are much less severe and may pass unrecognized, only being identified by screening for dipstick haematuria. In children recovery is the rule but in adults, often with comorbid conditions, the prognosis is significantly worse.
Management centres on loop diuretics plus treatment of the infection if still present, and additional hypotensive agents if required. Severe cases may require dialysis. High-dose corticosteroids have often been given in severe crescentic disease but there is no evidence that they are effective.
In children, recovery of renal function is often excellent, though long-term studies now suggest that it may represent a risk factor for the development of chronic kidney disease. When it occurs in developed societies it is often in older patients with comorbid conditions and atypical presentations. Resolution may be less complete than in children.
Left ventricular hypertrophy in chronic kidney disease
Authors: Zoccali Carmine , Bolignano Davide , Mallamaci Francesca
Published: June 2018

Alterations in left ventricular (LV) mass and geometry and LV dysfunction increase in prevalence from stage 2 to stage 5 in CKD. Nuclear magnetic resonance is the most accurate and precise technique for measuring LV mass and function in patients with heart disease. Quantitative echocardiography is still the most frequently used means of evaluating abnormalities in LV mass and function in CKD.
Anatomically, myocardial hypertrophy can be classified as concentric or eccentric. In concentric hypertrophy, the muscular component of the LV (LV wall) predominates over the cavity component (LV volume). Due to the higher thickness and myocardial fibrosis in patients with concentric LVH, ventricular compliance is reduced and the end-diastolic volume is small and insufficient to maintain cardiac output under varying physiological demands (diastolic dysfunction). In those with eccentric hypertrophy, tensile stress elongates myocardiocytes and increases LV end-diastolic volume. The LV walls are relatively thinner and with reduced ability to contract (systolic dysfunction).
LVH prevalence increases stepwisely as renal function deteriorates and 70–80% of patients with kidney failure present with established LVH which is of the concentric type in the majority. Volume overload and severe anaemia are, on the other hand, the major drivers of eccentric LVH. Even though LVH may regress after renal transplantation, the prevalence of LVH after transplantation remains close to that found in dialysis patients and a functioning renal graft should not be seen as a guarantee of LVH regression.
The vast majority of studies on cardiomyopathy in CKD are observational in nature and the number of controlled clinical trials in these patients is very small. Beta-blockers (carvedilol) and angiotensin receptors blockers improve LV performance and reduce mortality in kidney failure patients with LV dysfunction. Although current guidelines recommend implantable cardioverter-defibrillators in patients with ejection fraction less than 30%, mild to moderate symptoms of heart failure, and a life expectancy of more than 1 year, these devices are rarely offered to eligible CKD patients.
Conversion to nocturnal dialysis and to frequent dialysis schedules produces a marked improvement in LVH in patients on dialysis. More frequent and/or longer dialysis are recommended in dialysis patients with asymptomatic or symptomatic LV disorders if the organizational and financial resources are available.
Socioeconomic Disparities in Electronic Cigarette Use and Transitions from Smoking
Authors: Friedman Abigail S , Horn Samantha J L
Published: June 2018

Introduction

Socioeconomic disparities have been established for conventional cigarette use, but not for electronic cigarettes. This study estimates socioeconomic gradients in exclusive use of conventional cigarettes, electronic cigarettes, and dual use (ie, use of both products) among adults in the United States.

Methods

Analyses consider nationally representative data on 25- to 54-year-old respondents to the 2014–2016 National Health Interview Surveys (N = 50306). Demographically adjusted seemingly unrelated regression models estimate how two socioeconomic status measures—respondent education and household income—relate to current exclusive use of conventional cigarettes, electronic cigarettes, and dual use.

Results

Conventional cigarette use exhibits negative education and income gradients, consistent with existing research: −12.9 percentage points (confidence interval [CI]: −14.0, −11.8) if college educated, and −9.5 percentage points (CI: −10.9, −8.1) if household income exceeds 400% of the federal poverty level. These gradients are flatter for dual use (−1.4 [CI: −1.8, −0.9] and −1.9 [CI: −2.5, −1.2]), and statistically insignificant for electronic cigarette use (−0.03 [CI: −0.5, 0.4] and −0.3 [CI: −0.8, −0.2]). Limiting the sample to ever-smokers, higher education is associated with a 0.9 percentage point increase in likelihood of exclusive electronic cigarette use at interview (CI: 0.0, 1.9).

Conclusions

Education and income gradients in exclusive electronic cigarette use are small and statistically insignificant, contrasting with strong negative gradients in exclusive conventional cigarette use. Furthermore, more educated smokers are more likely to switch to exclusive e-cigarette use than less educated smokers. Such differential switching may exacerbate socioeconomic disparities in smoking-related morbidity and mortality, but lower the burden of tobacco-related disease.

Implications

Research has not yet established whether socioeconomic disparities in electronic cigarette (e-cigarette) use resemble those observed for conventional cigarettes. This article uses nationally representative data on US adults aged 25–54 to estimate income and education gradients in exclusive use of conventional cigarettes, e-cigarettes, and dual use. Both gradients are steep and negative for conventional cigarette use, but flat and statistically insignificant for e-cigarette use. Repeating the analysis among ever-smokers indicates that more educated smokers are more likely to transition toward exclusive e-cigarette use than less educated smokers. Such differential substitution may exacerbate disparities in smoking-related morbidity and mortality.
Analysis of Herman Goldstein Problem-Oriented Policing Awards from 1993-2017
Authors: Schnobrich-Davis Julie , Block Steven , Lupacchino Joseph
Published: June 2018

This article analysed the finalists and winners of the Herman Goldstein Problem-Oriented Policing projects from 1993 to 2017, which provides a sample of 153 cases. The article reflects on the changes in the problem-solving process overtime in regards to the nature of crime and quality of life problems addressed, the involvement of collaborative partners, the use of technology, and the level of sophistication of the assessment phase of the Scanning, Analysis, Response, and Assessment model. The processes used by the police agencies for each step of the problem-solving model (Scan, Analyse, Respond, Assess) were reviewed. Additionally, the authors measured the amount of outside collaboration for the project from crime analysts, researchers, and stakeholders. The issue of problem-solving being a viable strategy for 21st century policing is discussed.
Radiation Doses From the Norwegian Diet
Authors: Komperød Mari , Skuterud Lavrans
Published: June 2018

Ingestion doses between and within countries are expected to vary significantly due to differences in dietary habits and geographical variations in radionuclide concentrations. This paper presents the most comprehensive assessment to date of the effective radiation dose from the Norwegian diet, from natural as well as anthropogenic radionuclides. Ingestion doses to the Norwegian public are calculated using national dietary statistics and the most relevant radionuclide concentration data for the various food products. The age-weighted average effective dose received by the Norwegian population from the diet is estimated at 0.41 mSv y−1 from naturally occurring radionuclides and 0.010 mSv y−1 from anthropogenic radionuclides. This is approximately 50% higher than the estimated world average. Fish and shellfish is the food group that provides the largest dose contribution from the average Norwegian diet. Although the average dose from anthropogenic radionuclides today is low, the exposure may still be significant for certain critical groups—especially persons who consume large amounts of reindeer meat from the regions that received significant radioactive fallout after the Chernobyl accident. Furthermore, persons with high 222Rn concentrations in their drinking water are among those receiving the highest ingestion doses in Norway.
The Columbia Thyroid Eye Disease-Compressive Optic Neuropathy Diagnostic Formula
Authors: Callahan Alison B. , Campbell Ashley A. , Oropesa Susel , Baraban Aryeh , Kazim Michael
Published: June 2018

Purpose:

Diagnosing thyroid eye disease–compressive optic neuropathy (TED–CON) is challenging, particularly in cases lacking a relative afferent pupillary defect. Large case series of TED–CON patients and accessible diagnostic tools are lacking in the current literature. This study aims to create a mathematical formula that accurately predicts the presence or absence of CON based on the most salient clinical measures of optic neuropathy.

Methods:

A retrospective case series compares 108 patients (216 orbits) with either unilateral or bilateral TED–CON and 41 age-matched patients (82 orbits) with noncompressive TED. Utilizing clinical variables assessing optic nerve function and/or risk of compressive disease, and with the aid of generalized linear regression modeling, the authors create a mathematical formula that weighs the relative contribution of each clinical variable in the overall prediction of CON.

Results:

Data from 213 orbits in 110 patients derived the formula: y = −0.69 + 2.58 × (afferent pupillary defect) − 0.31 × (summed limitation of ductions) − 0.2 × (mean deviation on Humphrey visual field testing) − 0.02 × (% color plates). This accurately predicted the presence of CON (y > 0) versus non-CON (y < 0) in 82% of cases with 83% sensitivity and 81% specificity. When there was no relative afferent pupillary defect, which was the case in 63% of CON orbits, the formula correctly predicted CON in 78% of orbits with 73% sensitivity and 83% specificity.

Conclusions:

The authors developed a mathematical formula, the Columbia TED-CON Diagnostic Formula (CTD Formula), that can help guide clinicians in accurately diagnosing TED–CON, particularly in the presence of bilateral disease and when no relative afferent pupillary defect is present.
Multivariate pattern classification of brain white matter connectivity predicts classic trigeminal neuralgia
Authors: Zhong Jidan , Chen David Qixiang , Hung Peter Shih-Ping , Hayes Dave J. , Liang Kevin E. , Davis Karen D. , Hodaie Mojgan
Published: June 2018

Trigeminal neuralgia (TN) is a severe form of chronic facial neuropathic pain. Increasing interest in the neuroimaging of pain has highlighted changes in the root entry zone in TN, but also group-level central nervous system gray and white matter (WM) abnormalities. Group differences in neuroimaging data are frequently evaluated with univariate statistics; however, this approach is limited because it is based on single, or clusters of, voxels. By contrast, multivariate pattern analyses consider all the model's neuroanatomical features to capture a specific distributed spatial pattern. This approach has potential use as a prediction tool at the individual level. We hypothesized that a multivariate pattern classification method can distinguish specific patterns of abnormal WM connectivity of classic TN from healthy controls (HCs). Diffusion-weighted scans in 23 right-sided TN and matched controls were processed to extract whole-brain interregional streamlines. We used a linear support vector machine algorithm to differentiate interregional normalized streamline count between TN and HC. This algorithm successfully differentiated between TN and HC with an accuracy of 88%. The structural pattern emphasized WM connectivity of regions that subserve sensory, affective, and cognitive dimensions of pain, including the insula, precuneus, inferior and superior parietal lobules, and inferior and medial orbital frontal gyri. Normalized streamline counts were associated with longer pain duration and WM metric abnormality between the connections. This study demonstrates that machine-learning algorithms can detect characteristic patterns of structural alterations in TN and highlights the role of structural brain imaging for identification of neuroanatomical features associated with neuropathic pain disorders.
Patterns of recovery from pain after cesarean delivery
Authors: Booth Jessica L. , Sharpe Emily E. , Houle Timothy T. , Harris Lynnette , Curry Regina S. , Aschenbrenner Carol A. , Eisenach James C.
Published: June 2018

We know very little about the change in pain in the first 2 months after surgery. To address this gap, we studied 530 women scheduled for elective cesarean delivery who completed daily pain diaries for 2 months after surgery through text messaging. Over 82% of subjects missed fewer than 10 diary entries and were included in the analysis. Completers were more likely to be Caucasian, nonsmokers, and with fewer previous pregnancies than noncompleters. Daily worst pain intensity ratings for the previous 24 hours were fit to a log(time) function and allowed to change to a different function up to 3 times according to a Bayesian criterion. All women had at least one change point, occurring 22 ± 9 days postoperatively, and 81% of women had only one change, most commonly to a linear function at 0 pain. Approximately 9% of women were predicted to have pain 2 months after surgery, similar to previous observations. Cluster analysis revealed 6 trajectories of recovery from pain. Predictors of cluster membership included severity of acute pain, perceived stress, surgical factors, and smoking status. These data demonstrate feasibility but considerable challenges to this approach to data acquisition. The form of the initial process of recovery from pain is common to all women, with divergence of patterns at 2 to 4 weeks after cesarean delivery. The change-point model accurately predicts recovery from pain; its parameters can be used to assess predictors of speed of recovery; and it may be useful for future observational, forecasting, and interventional trials.
Improving herpes zoster vaccine rates: The impact of a targeted educational program
Authors: O'Donnell Margaret , Shurpin Kathleen , Janotha Brenda
Published: June 2018

Background and purpose:

Despite demonstrated efficacy, the utilization of herpes zoster vaccine (HZV), recommended by the Centers for Disease Control (CDC) for all immunocompetent adults aged above 60 years, is low (31%). The aim of this study was to identify nurse practitioner (NP) barriers to HZV administration and then to use these results to develop and evaluate the outcomes of an educational program.

Methods:

This study used a two-phase design. In Phase I, barriers that obstruct the provision of HZV were identified and NPs were surveyed to determine current HZV practice. The second phase used a quasiexperimental pretest–posttest design to evaluate the impact of the constructed program.

Conclusions:

In Phase I, NYS Primary Care NPs with practice years ranging from 1 to 24, who reported working in practice sites that ranged from 1 to 20 providers, possessed limited knowledge of the vaccine, especially, the financial aspects of the vaccination such as up-front cost (46%), cost to patients (39%), and reimbursement (29%), resulting in fewer provider recommendations. In Phase II, a paired-samples t test revealed a statistically significant difference between pretest scores (mean = 3.4, SD = 1.2) and posttest scores (mean = 4.7, SD = 1.3) on the knowledge survey, t (37) = −7.1, p < .0, demonstrating NPs' improved understanding of HZV.

Implications for practice:

Nurse practitioners will increase compliance with the CDC recommendations for HZV administration.
Analysis of Healthcare Institutional Costs of Pediatric Home Parenteral Nutrition Central Line Infections
Authors: Raphael Bram P. , Hazekamp Christina , Samnaliev Mihail , Ozonoff Al
Published: June 2018

Background:

Although previous literature suggests home parenteral nutrition (HPN)–dependent children experience frequent complications like community‐acquired central line‐associated bloodstream infections (CLABSI), few studies have characterized the cost.

Objective:

The aim of this study was to evaluate institutional cost of community‐acquired CLABSI in pediatric patients with HPN.

Methods:

This is a single‐center retrospective review of institutional costs for patients with HPN with community‐acquired CLABSI at a tertiary care children's hospital. Inclusion was age 18 years or less between October 2011 and April 2016. Exclusions were death during hospitalization and readmission within 2 days of discharge. Patient‐level factors were compared between high‐cost group and all others using Welch 2‐sample t test and analysis of variance. Multivariable logistic regression was used to determine predictors of higher cost.

Results:

There were 176 CLABSI admissions among 68 patients during the study period (median 2 hospitalizations per patients). The mean cost and length of stay per hospital admission are $28,375 (2015 US dollars) and 8 days, and both were associated with intensive care unit admission (ICU), central venous catheter removal, private insurance, and age <2 years at admission. Nine percent of patients were classified as “super‐utilizers” whose 54 hospitalizations accounted for 28% of total institutional costs.

Conclusions:

Among pediatric patients with HPN, community‐acquired CLABSI is associated with significant cost and length of stay. Healthcare utilization is disproportionately concentrated in a small number of patients. These study findings may help inform cost analysis for future CLABSI prevention strategies.
Rehabilitation for Cancer Survivors
Authors: Anwar Sumadi Lukman , Adistyawan Guritno , Wulaningsih Wahyu , Gutenbrunner Christoph , Nugraha Boya
Published: June 2018

Cancer diagnosis often substantially affects patient's physical, psychological, and emotional status. Most patients with cancer experience declining of energy, activity levels, social-cultural participation, and relationships. In addition, cancer progression and adverse effects of aggressive cancer treatment often cause debilitating pain, fatigue, weakness, joint stiffness, depression, emotional instability, limited mobility, poor nutritional status, skin breakdown, bowel dysfunction, swallowing difficulty, and lymphedema leading into functional impairment and disability that can be addressed through rehabilitation care. Comprehensive care models by involving cancer rehabilitation have resulted in significant improvement of patient's quality of life. Although cancer rehabilitation has been implemented in many high-income countries, it is either not yet or suboptimally delivered in most low- and middle-income countries. In this review, we discussed gaps regarding cancer rehabilitation services and identified opportunities to improve quality of cancer care in developing countries. Future collaborations among international organizations and stakeholders of health care delivery systems are required to initiate and improve high-quality cancer rehabilitation in the developing countries.
When the Injury's Healing Process Meets the Needs of a Top-Level Volleyball Player
Authors: Checcarelli Daniele , Zampolini Mauro , Berloco Michele , Fusco Claudia , Özçakar Levent
Published: June 2018

Managing top-level athlete's recovery after an injury is very complicated because it requires a challenging combination of clinical and social/professional aspects with the need to return as soon as possible to sports play. Herein, we report a top-level volleyball player for whom a finger splint combined with a custom made thermoplastic protection was used for the conservative management of a Mallet fracture reinjury. This way our player continued training and competitions in contrast to conventional rehabilitation protocols, which suggest to avoid new traumas until the healing phase is completed. After 8 wks, we obtained the fracture healing and a complete functional recovery without major medical complications. From our results, we suggest that novel treatment strategies or modification of conventional rehabilitation protocols are worth consideration for the management of high-level sports players' injuries. However, new clinical studies with a larger sample can compare these results with those resulting from both surgical procedures and from immobilization and rest as well.
Sex Education and HIV Testing Among Young Men Who Have Sex With Men: Findings From the 2006–2010 and 2011–2015 National Survey of Family Growth
Authors: Pierce Jace D. , Ylitalo Kelly R. , Lanning Beth A. , Limbers Christine C.
Published: June 2018

Background:

Young men who have sex with men (YMSM) are disproportionally affected by HIV and exhibit low levels of HIV testing. The purpose of this study was to examine the relationship between sex education and subsequent HIV testing among YMSM.

Methods:

Data from sexually active men aged 15–24 years at interview in the 2006–2010 or 2011–2015 National Survey of Family Growth. Sex education included 3 contexts [formal institutions (eg, schools), parents, and health care providers] and specific topics. Outcome variables were ever- and recent-HIV testing. Multivariate models were adjusted for sociodemographics, and data were weighted to account for the complex survey sampling design.

Results:

A total of 323 sexually active YMSM met inclusion criteria. Overall, 42.4% had ever-tested for HIV and 16.9% tested in the previous 12 months. YMSM were more likely to have ever-tested for HIV if they talked with a parent/guardian about how to prevent HIV/AIDS [adjusted prevalence ratio (aPR) = 1.48; 95% confidence interval (CI): 1.07 to 2.06], talked with a health care provider about how HIV/AIDs is transmitted (aPR = 1.64; 95% CI: 1.13 to 2.38), sexually transmitted diseases (aPR = 1.49; 95% CI: 1.02 to 2.19), condom use (aPR = 1.61; 95% CI: 1.13 to 2.30), and the importance of HIV testing (aPR = 1.83; 95% CI: 1.22 to 2.73).

Conclusions:

Tailored sex education by parent(s) and health care providers related to HIV/AIDS seems to significantly increase the likelihood of HIV testing among YMSM.
Torticollis Caused by Nontraumatic Craniovertebral Junction Abnormalities
Authors: Park Sunghoon , Woo Ji-Eun , Kim Sanghyun , Yim Shin-Young
Published: June 2018

Torticollis could be the only symptom and sign of craniovertebral junction (CVJ) abnormality. It could be difficult to identify CVJ abnormality as a cause of torticollis due to their rarity, especially for the subjects with torticollis caused by nontraumatic CVJ abnormalities. There has been no report to focus on nontraumatic CVJ abnormalities as a cause of torticollis. The objective of this study was to report 27 patients of torticollis caused by nontraumatic CVJ abnormalities, with the aim of helping clinicians to identify nontraumatic CVJ abnormalities as a cause of torticollis. This is a retrospective cohort study including 27 subjects who had torticollis caused by nontraumatic CVJ abnormalities. The CVJ was examined in terms of atlanto-occipital angle, atlanto-axial angle, and lateral and anterior atlanto-dens intervals for the evaluation of occipital condylar hypoplasia, rotation of atlanto-axial joint, and lateral and anterior shift of the dens, respectively. Abnormalities of the lower cervical or thoracic spine were also evaluated. Occipital condylar hypoplasia, rotation of atlanto-axial joint, and lateral shift of the dens were the most common CVJ abnormalities. The 18.5% of the subjects had concurrent anomalies of lower cervical or thoracic vertebrae along with CVJ abnormalities. Each subject had 2.22 ± 1.10 types of CVJ abnormalities on average. In conclusion, comprehensive evaluation of CVJ abnormalities is recommended for differential diagnosis of subjects with unexplained torticollis. Once CVJ abnormalities are identified, concurrent abnormalities of other vertebrae need to be evaluated.
Influence of activation pattern estimates and statistical significance tests in fMRI decoding analysis
Authors: Arco Juan E. , González-García Carlos , Díaz-Gutiérrez Paloma , Ramírez Javier , Ruz María
Published: June 2018

The use of Multi-Voxel Pattern Analysis (MVPA) has increased considerably in recent functional magnetic resonance imaging studies. A crucial step consists in the choice of methods for the estimation of responses and their statistical significance. However, a systematic comparison of these and their adequacy to predominant experimental design is missing.

In the current study, we compared three pattern estimation methods: Least-Squares Unitary (LSU), based on run-wise estimation, Least-Squares All (LSA) and Least-Squares Separate (LSS), which rely on trial-wise estimation. We compared the efficiency of these methods in an experiment where sustained activity had to be isolated from zero-duration events as well as in a block-design approach and in an event-related design. We evaluated the sensitivity of the t-test in comparison with two non-parametric methods based on permutation testing: one proposed in Stelzer et al. (2013), equivalent to performing a permutation in each voxel separately and the Threshold-Free Cluster Enhancement (Smith and Nichols, 2009).

LSS resulted the most accurate approach to address the large overlap of signal among close events in the event-related designs. We found a larger sensitivity of Stelzer’s method in all settings, especially in the event-related designs, where voxels close to surpass the statistical threshold with the other approaches were now marked as informative regions.

Our results provide evidence that LSS is the most accurate approach for unmixing events with different duration and large overlap of signal, consistent with previous studies showing better handling of collinearity in LSS. Moreover, Stelzer’s potentiates this better estimation with its larger sensitivity.
An unexpectedly effective Monte Carlo technique for the RNA inverse folding problem
Authors: Portela Fernando
Published: June 2018

Solving the RNA inverse folding problem, also known as the RNA design problem, is critical to advance several scientific fields like bioengineering, yet existing approaches have had limited success. The problem has several features that resist traditional computational techniques, such as its exponential complexity and the chaotic behavior of its cost function. Although some state-of-the-art AI approaches have reported promising results, all existing computational methods substantially underperform expert human designers. I combine a different technique, Nested Monte Carlo Search (NMCS), with domain-specific knowledge to create an algorithm that outperforms all prior published methods by wide margins and solves 95 of the 100 puzzles listed in a recently proposed RNA solving difficulty benchmark.
Quantification of nuclear protein dynamics reveals chromatin remodeling during acute protein degradation
Authors: Federation Alexander J. , Nandakumar Vivek , Wang Hao , Searle Brian C. , Pino Lindsay K. , Merrihew Gennifer , Ting Ying S. , Howard Nicholas , Kutyavin Tanya , MacCoss Michael J. , Stamatoyannopoulos John A.
Published: June 2018

Sequencing-based technologies cannot measure post-transcriptional dynamics of the nuclear proteome, but unbiased mass-spectrometry measurements of chromatin-associated proteins remain difficult. In this work, we have combined facile nuclear sub-fractionation approaches with data-independent acquisition mass spectrometry to improve detection and quantification of nuclear proteins in human cells and tissues. Nuclei are isolated and subjected to a series of extraction conditions that enrich for nucleoplasm, euchromatin, heterochromatin and nuclear-membrane associated proteins. Using this approach, we can measure peptides from over 70% of the expressed nuclear proteome. As we are physically separating chromatin compartments prior to analysis, proteins can be assigned into functional chromatin environments to illuminate systems-wide nuclear protein dynamics. The integrity of nuclear sub-compartments were validated with immunofluorescence, which confirms the presence of key markers during chromatin extraction. We then apply this method to study the nuclear proteome-wide response to pharmacological degradation of the BET bromodomain proteins. BET degradation leads to widespread changes in chromatin composition, and we discover global HDAC1/2-mediated remodeling of chromatin previously bound by BET bromodomains. In summary, we have developed a technology for reproducible, comprehensive characterization of the nuclear proteome to observe the systems-wide nuclear protein dynamics.
Transfer learning with deep convolutional neural networks for classifying cellular morphological changes
Authors: Kensert Alexander , Harrison Philip J , Spjuth Ola
Published: June 2018

Quantification and identification of cellular phenotypes from high content microscopy images have proven to be very useful for understanding biological activity in response to different drug treatments. The traditional approach has been to use classical image analysis to quantify changes in cell morphology, which requires several non-trivial and independent analysis steps. Recently convolutional neural networks have emerged as a compelling alternative, offering good predictive performance and the possibility to replace traditional workflows with a single network architecture. In this study we applied the pre-trained deep convolutional neural networks ResNet50, InceptionV3 and InceptionResnetV2 to predict cell mechanisms of action in response to chemical perturbations for two cell profiling datasets from the Broad Bioimage Benchmark Collection. These networks were pre-trained on ImageNet enabling much quicker model training. We obtain higher predictive accuracy than previously reported, between 95 and 97% based on “leave-one-compound-out” cross-validation. The ability to quickly and accurately distinguish between different cell morphologies from a scarce amount of labelled data illustrates the combined benefit of transfer learning and deep convolutional neural networks for interrogating cell-based images.
The radial expression of dorsal-ventral patterning genes in placozoans,Trichoplax adhaerens,argues for an oral-aboral axis
Authors: DuBuc Timothy Q. , Bobkov Yuriy , Ryan Joseph , Martindale Mark Q.
Published: June 2018

The placozoans are a morphologically simplistic group of marine animals found globally in tropical and subtropical environments. They consist of a single named species,Trichoplax adhaerensand have roughly six morphologically distinct cell types. With a sequenced genome, a limited number of cell-types and a simple flattened morphology,Trichoplaxis an ideal model organism to understand cellular dynamics and tissue patterning in the first animals. Using new approaches for identification of gene expression patterns this research looks at the relationship of Chordin/TgfB signaling and the axial patterning system of Placozoa. Our results suggest that placozoans have an oral-aboral axis similar to cnidarians and that the parahoxozoan ancestor (common ancestor of Placozoa and Cnidaria) was likely radially symmetric.
Holistic optimization of an RNA-seq workflow for multi-threaded environments
Authors: Hung Ling-Hong , Lloyd Wes , Agumbe Sridhar Radhika , Athmalingam Ravishankar Saranya Devi , Xiong Yuguang , Sobie Eric , Yeung Ka Yee
Published: June 2018

For many next-generation sequencing pipelines, the most computationally intensive step is the alignment of reads to a reference sequence. As a result, alignment software such as the Burrows-Wheeler Aligner (BWA) is optimized for speed and and is often executed in parallel on the cloud. However, there are other less demanding steps that can also be optimized and significantly increase the speed especially when using many threads. We demonstrate this using a Unique-molecular-identifier (UMI) RNA sequencing pipeline consisting of 3 steps: split, align, and merge. Optimization of all three steps yields a 40% increase in speed when executed using a single thread. However, when executed using 16 threads, we observe a 4-fold improvement over the original parallel imple-mentation and more than an 8-fold improvement over the original single-threaded implementation. In contrast, optimizing only the alignment step results in just a 13% improvement over the original parallel workflow using 16 threads.
Stress-responsive and metabolic gene regulation are altered in low S-adenosylmethionine
Authors: Ding Wei , Higgins Daniel P , Yadav Dilip K. , Pukklia-Worley Read , Walker Amy K
Published: June 2018

S-adenosylmethionine (SAM) is the methyl donor that modifies proteins such as histones, nucleic acids and produces phosphatidylcholine. Thus variations in SAM levels could affect processes from lipogenesis to epigenetic gene regulation. SAM is hypothesized to link metabolism and chromatin modification, however, its role in acute gene regulation is poorly understood. We recently found that Caenorhabditis elegans with reduced SAM had deficiencies in bacterial-induced H3K4 trimethylation at selected pathogen-response genes, decreasing their expression and limiting survival on the pathogen Pseudomonas aeruginosa. This led us to the hypothesis that SAM may be generally required stress-responsive transcription. Here we show that C. elegans with low SAM fail to activate genome-wide transcriptional programs when exposed to bacterial or xenotoxic stress. However, heat shock responses were unaffected. We also investigated the role of two H3K4 methyltransferases that use SAM, set-2/SET1, and set-16/MLL and found that set-2/SET1 has a specific requirement in bacterial stress responses, whereas set-16/MLL was required for survival in all three stresses. These results define a role for SAM and H3K4 methyltransferases in the acute genome-wide remodeling of gene expression in response to stress. Finally, we find that the ability to modify metabolic gene expression correlates with enhanced survival in stress conditions.
Scalable methods for analyzing and visualizing phylogenetic placement of metagenomic samples
Authors: Czech Lucas , Stamatakis Alexandros
Published: June 2018

1

The exponential decrease in molecular sequencing cost generates unprecedented amounts of data. Hence, scalable methods to analyze these data are required. Phylogenetic (or Evolutionary) Placement methods identify the evolutionary provenance of anonymous sequences with respect to a given reference phylogeny. This increasingly popular method is deployed for scrutinizing metagenomic samples from environments such as water, soil, or the human gut.

Here, we present novel and, more importantly, highly scalable methods for analyzing phylogenetic placements of metagenomic samples. More specifically, we introduce methods for (a) visualizing differences between samples and their correlation with associated meta-data on the reference phylogeny, (b) clustering similar samples using a variant of the fc-means method, and (c) finding phylogenetic factors using an adaptation of the Phylofactorization method. These methods enable to interpret metagenomic data in a phylogenetic context, to find patterns in the data, and to identify branches of the phylogeny that are driving these patterns.

To demonstrate the scalability and utility of our methods, as well as to provide exemplary interpretations of our methods, we applied them to 3 publicly available datasets comprising 9782 samples with a total of approximately 168 million sequences. The results indicate that new biological insights can be attained via our methods.
Haplotype assembly of autotetraploid potato using integer linear programming
Authors: Siragusa Enrico , Finkers Richard , Parida Laxmi
Published: June 2018

Haplotype assembly of polyploids is an open issue in plant genomics. Recent experimental studies on highly heterozygous autotetraploid potato have shown that available methods are not delivering satisfying results in practice. We propose an optimal method to assemble haplotypes of highly heterozygous polyploids from Illumina short sequencing reads. Our method is based on a generalization of the existing minimum fragment removal (MFR) model to the polyploid case and on new integer linear programs (ILPs) to reconstruct optimal haplotypes. We validate our methods experimentally by means of a combined evaluation on simulated and real data based on 83 previously sequenced autotetraploid potato cultivars. Results on simulated data show that our methods produce highly accurate haplotype assemblies, while results on real data confirm a sensible improvement over the state of the art. Binaries for Linux are available at: http://github.com/ComputationalGenomics/HaplotypeAssembler.
A new method for detecting autocorrelation of evolutionary rates in large phylogenies
Authors: Tao Qiqing , Tamura Koichiro , Battistuzzi Fabia , Kumar Sudhir
Published: June 2018

New species arise from pre-existing species and inherit similar genomes and environments. This predicts greater similarity of mutation rates and the tempo of molecular evolution between direct ancestors and descendants, resulting in autocorrelation of evolutionary rates within lineages in the tree of life. Surprisingly, molecular sequence data have not confirmed this expectation, possibly because available methods lack power to detect autocorrelated rates. Here we present a machine learning method to detect the presence evolutionary rate autocorrelation in large phylogenies. The new method is computationally efficient and performs better than the available state-of-the-art methods. Application of the new method reveals extensive rate autocorrelation in DNA and amino acid sequence evolution of mammals, birds, insects, metazoans, plants, fungi, and prokaryotes. Therefore, rate autocorrelation is a common phenomenon throughout the tree of life. These findings suggest concordance between molecular and non-molecular evolutionary patterns and will foster unbiased and precise dating of the tree of life.
Computation of history-dependent mechanical damage of axonal fiber tracts in the brain: towards tracking sub-concussive and occupational damage to the brain
Authors: Gerber Jesse I. , Garimella Harsha T. , Kraft Reuben H.
Published: June 2018

Finite element models are frequently used to simulate traumatic brain injuries. However, current models are unable to capture the progressive damage caused by repeated head trauma. In this work, we propose a method for computing the history-dependent mechanical damage of axonal fiber bundle tracts in the brain. Through the introduction of multiple damage models, we provide the ability to link consecutive head impact simulations, so that potential injury to the brain can be tracked over time. In addition, internal damage variables are used to degrade the mechanical response of each axonal fiber bundle element. As a result, the stiffness of the aggregate tissue decreases as damage evolves. To counteract this degenerative process, we have also introduced a preliminary healing model that reverses the accumulated damage, based on a user-specified healing duration. Using two detailed examples, we demonstrate that damage produces a significant decrease in fiber stress, which ultimately propagates to the tissue level and produces a measurable decrease in overall stiffness. These results suggest that damage modeling has the potential to enhance current brain simulation techniques and lead to new insights, especially in the study of repetitive head injuries.
Local-community network automata modelling based on length-three-paths for prediction of complex network structures in protein interactomes, food webs and more
Authors: Muscoloni Alessandro , Abdelhamid Ilyes , Cannistraci Carlo Vittorio
Published: June 2018

From nests to nets intricate wiring diagrams surround the birth and the death of life. Here we show that the same rule of complex network self-organization is valid across different physical scales and allows to predict protein interactions, food web trophic relations and world trade network transitions. This rule, which we named CH2-L3, is a network automaton that is based on paths of length-three and that maximizes internal links in local communities and minimizes external ones, according to a mechanistic model essentially driven by topological neighbourhood information.
A Combined Numerical and Experimental Investigation of Localized Electroporation-based Transfection and Sampling
Authors: Mukherjee Prithvijit , Nathamgari S. Shiva P. , Kessler John A. , Espinosa Horacio D.
Published: June 2018

Localized electroporation has evolved as an effective technology for the delivery of foreign molecules into adherent cells, and more recently, for the sampling of cytosolic content from a small population of cells. Unlike bulk electroporation, where the electric field is poorly controlled, localized electroporation benefits from the spatial localization of the electric field on a small areal fraction of the cell membrane, resulting in efficient molecular transport and high cell-viability. Although there have been numerous experimental reports, a mechanistic understanding of the different parameters involved in localized electroporation is lacking. In this work, we developed a multiphysics model that a) predicts the electro-pore distribution in response to the local transmembrane potential and b) calculates the molecular transport into and out of the cell based on the predicted pore-sizes. Using the model, we identify that cell membrane tension plays a crucial role in enhancing both the amount and the uniformity of molecular transport, particularly for large proteins and plasmids. We qualitatively validate the model predictions by delivering large molecules (fluorescent-tagged bovine serum albumin and mCherry encoding plasmid) and by sampling an exogeneous protein (tdTomato) in an engineered cell line. The findings presented here should inform the future design of microfluidic devices for localized electroporation based sampling, eventually paving the way for temporal, single-cell analysis.
In vitrocommunity synergy between bacterial soil isolates can be facilitated by pH stabilisation of the environment
Authors: Herschend Jakob , Koren Klaus , Røder Henriette L. , Brejnrod Asker , Kühl Michael , Burmølle Mette
Published: June 2018

Composition and development of naturally occurring microbial communities is defined by a complex interplay between the community and the surrounding environment and by interactions between community members. Intriguingly, these interactions can in some cases cause community synergies where the community is able to outperform it single species constituents. However, the underlying mechanisms driving community interactions are often unknown and difficult to identify due to high community complexity. Here we show how pH stabilisation of the environment through the metabolic activity of specific community members acts as a positive inter-species interaction drivingin vitrocommunity synergy in a model consortium of four co-isolated soil bacteria:Microbacterium oxydans,Xanthomonas retroflexus,Stenotrophomonas rhizophilaandPaenibacillus amylolyticus. Using micro-sensor pH measurements to show how individual species change the local pH micro-environment, and how co-cultivation leads to a stabilised pH regime over time. Specifically,in vitroacid production fromPaenibacillus amylolyticusand alkali production primarily fromXanthomonas retroflexuslead to an overall pH stabilisation of the local environment over time, which in turn resulted in enhanced community growth. This specific type of interspecies interaction was found to be highly dependent on media type and media concentration, however similar pH drift from the individual species could be observed across media variants.

Importance

We show thatin vitrometabolic activity of individual members of a synthetic, co- isolated model community presenting community synergistic growth arises through the inter-species interaction of pH stabilization of the community micro-environment. The observed inter-species interaction is highly media specific and most pronounced under high nutrient availability. This adds to the growing diversity of identified community interactions leading to enhanced community growth.