bluuebunny/crossref_metadata_2025 huggingface dataset:
Inappropriately Timed Pediatric Orthopaedic Referrals From the Emergency Department Result in Unnecessary Appointments and Financial Burden for Patients
Authors: Jackson Taylor J. , Blumberg Todd J. , Shah Apurva S. , Sankar Wudbhav N.
Published: January 2018

Background:

Musculoskeletal injuries are among the most common reasons for emergency department (ED) visits in the pediatric population. Many such injuries can be managed with a single follow-up outpatient visit. However, untimely (ie, premature) referrals by emergency physicians to orthopaedic surgeons are common and may inadvertently create need for a second visit, generating unnecessary expenditures. We sought to elucidate the cost of premature musculoskeletal follow-up visits to the patients, families, and the health care system.

Methods:

We performed a retrospective review of pediatric patients with acute musculoskeletal injuries referred from our ED (without a formal orthopaedic consult) to our outpatient clinic. Patients were retrospectively reviewed in a consecutive fashion. The appropriateness of the recommended follow-up time interval was determined for each patient, and the direct and indirect cost of the inappropriate services were calculated utilizing a combination of traditional cost accounting techniques and time-driven activity-based costing. The characteristics of patients with appropriate and untimely follow-up referrals were compared.

Results:

Two hundred consecutive referrals from the ED were reviewed. Overall, 96.5% of the follow-up visits recommended by the ED were premature, which led 106 (53%) patients to require a second visit to complete their clinical care. Patients who required a second visit were significantly younger (P=0.005), more likely to be male (P=0.042), more likely to have a fracture (P<0.001), and less likely to have a sprain (P<0.001) or dislocation/subluxation (P<0.001). Over 40% of second visits were accounted for by 3 diagnoses (distal radius buckle fractures, nondisplaced Salter-Harris 1 fractures of the ankle, and buckle fractures of the finger). Across the whole cohort, the total financial impact of untimely visits was $36,265.78, representing an average cost of $342.93 per patient.

Conclusions:

Untimely referrals for follow-up of acute pediatric musculoskeletal conditions are very common and represent a significant financial burden to patients, families, and the health care system. Over 40% of unnecessary visits resulted from just 3 diagnoses. Improved orthopaedic follow-up guidelines, particularly for these readily recognizable conditions, and feedback to referring providers may reduce poorly timed clinic visits and decrease costs in the treatment of common orthopaedic injuries in pediatric patients.

Level of Evidence:

Level III.
Indications, Postoperative Management, and Advances in Ankle Fracture Fixation
Authors: Alluri Ram K. , Tan Eric W.
Published: January 2018

Ankle fracture management continues to be an evolving process, particularly with regards to identifying unstable fracture patterns, improving fixation techniques, and optimizing postoperative management. The most accurate method to identify unstable ankle fractures based on preoperative imaging remains controversial and further prospective studies with functional outcomes and well-defined instability parameters are still needed. Several studies have investigated advanced fixation techniques, however, standard nonlocking, one-third tubular plates can still be used for the majority of fractures. Locking plates may provide a biomechanical advantage in patients with osteoporotic bone and intramedullary fibular nails may be beneficial in patients at risk for postoperative wound complications. With regards to postoperative management, the long-term benefit of early weight-bearing has yet to be proven and the need for venous thromboembolism prophylaxis remains without consensus and should be based on individual patient risk stratification.

Level of Evidence: See Instructions for Authors for a complete description of levels of evidence.
Bilateral Cochlear Implants: Maximizing Expected Outcomes
Authors: Wallis Kate E. , Blum Nathan J. , Waryasz Stephanie A. , Augustyn Marilyn
Published: January 2018

CASE:

Sonia is a 4 years 1 month-year-old girl with Waardenburg syndrome and bilateral sensorineural hearing loss who had bilateral cochlear implants at 2 years 7 months years of age. She is referred to Developmental-Behavioral Pediatrics by her speech/language pathologist because of concerns that her language skills are not progressing as expected after the cochlear implant. At the time of the implant, she communicated using approximately 20 signs and 1 spoken word (mama). At the time of the evaluation (18 months after the implant) she had approximately 70 spoken words (English and Spanish) and innumerable signs that she used to communicate. She could follow 1-step directions in English but had more difficulty after 2-step directions.

Sonia was born in Puerto Rico at 40 weeks gestation after an uncomplicated pregnancy. She failed her newborn hearing test and was given hearing aids that did not seem to help.

At age 2 years, Sonia, her mother, and younger sister moved to the United States where she was diagnosed with bilateral severe-to-profound hearing loss. Genetic testing led to a diagnosis of Waardenburg syndrome (group of genetic conditions that can cause hearing loss and changes in coloring [pigmentation] of the hair, skin, and eyes). She received bilateral cochlear implants 6 months later.

Sonia's mother is primarily Spanish-speaking and mostly communicates with her in Spanish or with gestures but has recently begun to learn American Sign Language (ASL). In a preschool program at a specialized school for the deaf, Sonia is learning both English and ASL. Sonia seems to prefer to use ASL to communicate.

Sonia receives speech and language therapy (SLT) 3 times per week (90 minutes total) individually in school and once per week within a group. She is also receiving outpatient SLT once per week. Therapy sessions are completed in English, with the aid of an ASL interpreter. Sonia's language scores remain low, with her receptive skills in the first percentile, and her expressive skills in the fifth percentile.

During her evaluation in Developmental and Behavioral Pediatrics, an ASL interpreter was present, and the examiner is a fluent Spanish speaker. Testing was completed through a combination of English, Spanish, and ASL. Sonia seemed to prefer ASL to communicate, although she used some English words with errors of pronunciation. On the Beery Visual-Motor Integration Test, she obtained a standard score of 95. Parent and teacher rating scales were not significant for symptoms of attention-deficit/hyperactivity disorder.

What factors are contributing to her slow language acquisition and how would you modify her treatment plan?
INCIDENCE AND LONG-TERM VISUAL ACUITY OUTCOMES OF RETINAL PIGMENT EPITHELIUM TEARS AFTER INTRAVITREAL ANTI–VASCULAR ENDOTHELIAL GROWTH FACTOR TREATMENT OF NEOVASCULAR AGE-RELATED MACULAR DEGENERATION
Authors: Vazquez-Alfageme Clara , Nicholson Luke , Hamilton Robin D. , Patel Praveen J.
Published: January 2018

Purpose:

To report the incidence of retinal pigment epithelium tears in eyes treated with aflibercept for neovascular age-related macular degeneration and compare it with ranibizumab, and to describe long-term visual outcomes of retinal pigment epithelium tears after intensive anti–vascular endothelial growth factor treatment.

Methods:

Retrospective analysis of clinical charts, spectral domain optical coherence tomography and fundus fluorescein angiography imaging of consecutive naive patients treated with intravitreal aflibercept or ranibizumab for neovascular age-related macular degeneration.

Results:

Eight hundred consecutive eyes were included in the study (300 treated with ranibizumab and 500 with aflibercept) with 34.0 ± 9.1 months of follow-up. The incidence of tears in the aflibercept group was 3.2% and 2.3% after ranibizumab (P = 0.52). Twenty-nine eyes with retinal pigment epithelium tears were followed for a mean of 30.76 months. Visual acuity at baseline was 20/100 (50.7 ± 19.3 Early Treatment Diabetic Retinopathy Study letters) and 20/200 (36.1 ± 26.1 Early Treatment Diabetic Retinopathy Study letters) at the end of follow-up. The mean number of injection was 7.3 at 12 months and 13.9 ± 8.1 at the end of the study. The number of injections positively correlated with the final visual outcome.

Conclusion:

There was a low rate of retinal pigment epithelium tears after aflibercept injections, similar to ranibizumab. The correlation between the number of anti–vascular endothelial growth factors received and visual outcomes supports the need for continuing anti–vascular endothelial growth factor therapy.
Corneal Collagen Cross-Linking With Riboflavin and Ultraviolet A Light for Pediatric Keratoconus: Ten-Year Results
Authors: Mazzotta Cosimo , Traversi Claudio , Baiocchi Stefano , Bagaglia Simone , Caporossi Orsola , Villano Antonio , Caporossi Aldo
Published: January 2018

Purpose:

To assess the 10-year follow-up efficacy and safety of riboflavin ultraviolet A–induced cross-linking (CXL) in a population of pediatric patients aged 18 years and younger with progressive keratoconus (KC).

Methods:

The prospective longitudinal cohort study included 62 eyes of 47 keratoconic patients undergoing epithelium-off CXL who completed 10-year follow-up. The surgical procedure was performed in all patients according to the Siena (Dresden modified) protocol. Evaluation included uncorrected distance visual acuity, corrected distance visual acuity, Scheimpflug corneal tomography, and optical coherence tomography demarcation line measurement. Follow-up measurements taken up to 10 years after treatment were compared with baseline values, and statistical analysis was performed using a 2-tailed paired sample Student t test.

Results:

Uncorrected distance visual acuity and corrected distance visual acuity improved from 0.45 to 0.23 logarithm of the minimum angle resolution (P = 0.0001) and from 0.14 to 0.1 logarithm of the minimum angle resolution (P = 0.019). KC stability was recorded after 10 years of follow-up in nearly 80% of the patients. The overall 10-year follow-up progression rate was 24% including 13 eyes of 9 patients with Kmax progression over 1 diopter and 2 eyes of 2 patients who underwent corneal grafting.

Conclusions:

The study demonstrates the ability of CXL to slow down KC progression in pediatric patients, improving functional performance. Long-term stability may be correlated with CXL-induced delay in corneal collagen turnover and with spontaneous age-related KC stabilization. A 24% regression rate could be contemplated in the patients who were aged 15 years and younger at the time of inclusion in the treatment protocol.
Repeated Same-Day Versus Single Tomography Measurements of Keratoconic Eyes for Analysis of Disease Progression
Authors: Wonneberger Wolf , Sterner Bertil , MacLean Ulrika , Claesson Margareta , Zetterberg Madeleine
Published: January 2018

Purpose:

Corneal tomography is used to assess progression of keratoconus and to direct clinical decisions regarding corneal cross-linking. The purpose of this study was to analyze the variability of repeated Scheimpflug-tomography (Pentacam Classic; Oculus, Wetzlar, Germany) measurements of keratoconic eyes in a clinical setting and to assess the validity of such measurements as a clinical decision-making tool.

Methods:

Eighty keratoconic eyes of 45 patients (age range 16–32 years) were examined at baseline and after follow-up periods of 3 to 6 months using 3 consecutive tomography measurements at each visit. Minimum corneal thickness and anterior sagittal curvature map parameters were studied [simulated keratometry (K) astigmatism (SimKast); maximum simulated K-reading (SimKmax); average SimK (SimKave); maximum K-readings on the 3-mm (Kmax3) and 5-mm (Kmax5) rings; and maximum K-reading (Kmax)].

Results:

When comparing the first measurements at the first and second visits, respectively, 9% to 20% of eyes were classified as progressive depending on which parameter was chosen. Using the average of 3 consecutive measurements at each visit, 5% to 19% of eyes were classified as progressive. An increase in the SD of 3 consecutive measurements of SimKast (SD_SimKast) at the first visit of 1 diopter makes true progression of keratoconus 3.6 times more likely (odds ratio = 3.6; 95% confidence interval: 0.846–16.027; area under the curve = 0.70).

Conclusions:

The approach used to analyze progression in keratoconus, that is, single versus repeated measurements, may confer a great impact on the decision to perform corneal cross-linking treatment or not.
Exercise Capacity in Patients with the Total Artificial Heart
Authors: Canada Justin M. , Evans Ronald K. , Abbate Antonio , Arena Ross , Tang Daniel G. , Kasirajan Vigneshwar , Shah Keyur B.
Published: January 2018

There is a dearth of information regarding the functional abilities of patients with the total artificial heart (TAH). Increased utilization of the TAH and patient discharge to home with the portable unit necessitates a shift in focus to quality of life, which includes quantifying and ultimately optimizing functional capacity. To date, only single-patient case studies have described the exercise response of the TAH patient. Fourteen patients with the TAH underwent cardiopulmonary exercise testing with concurrent analysis of TAH device function. All device settings remained fixed during testing. Peak oxygen consumption (VO2; 0.872 L/min [interquartile range (IQR) = 0.828–1.100 L/min]), percent predicted peak VO2(36% [IQR = 32–42%]), and ventilatory anaerobic threshold (0.695 L/min [IQR = 0.542–0.845 L/min]) were markedly reduced in the TAH compared with predicted normal values. Determinants of VO2using device-generated hemodynamics revealed a blunted cardiac output (+9% increase) and exaggerated oxygen extraction with exercise. Peak VO2strongly correlated with resting (R = +0.548,p= 0.045), ventilatory anaerobic threshold (R = +0.780,p= 0.001), and peak exercise cardiac output (R = +0.672,p= 0.008). Patients with the TAH have significantly impaired exercise performance. The limitations to cardiopulmonary exercise testing performance appear to be related to limited ability of the pump to modulate output for activity and reduced oxygen carrying capacity.
Pathways to Congenital Syphilis Prevention: A Rapid Qualitative Assessment of Barriers, and the Public Health Response, in Caddo Parish, Louisiana
Authors: Kroeger Karen A. , Sangaramoorthy Thurka , Loosier Penny S. , Schmidt Rebecca , Gruber DeAnn
Published: January 2018

Background

Congenital syphilis (CS) disproportionately affects racial and ethnic minority women, especially in the US South. Although CS is relatively easy and inexpensive to prevent through screening and treatment of pregnant women, CS cases have continued to rise and are concentrated in relatively few US counties and states. In 2010, Louisiana had the highest case rate in the country for primary, secondary, and CS, with the highest number of CS cases in northwest Louisiana, where Shreveport is located.

Methods

We conducted qualitative interviews with community members (women and frontline providers) living in Caddo Parish to obtain their views about factors that negatively impact CS prevention.

Results

Participants described impediments in the pathways for prevention of CS. Lack of sexual and reproductive health education, discontinuities and fragmentation in health care insurance coverage, a dearth of referral points for prenatal care, and difficulty finding prenatal care providers who accept Medicaid can delay timely and adequate care for pregnant women. Participants reported that low reimbursement for necessary injections and difficulty obtaining required medication challenged efforts to screen and treat pregnant women according to guidelines.

Conclusions

Although CS is easily prevented, health system and policy obstacles in pathways to CS prevention and care may need remediation at state and local levels.
Pediatric Appendicitis
Authors: Drapkin Zachary , Dunnick Jennifer , Madsen Troy E. , Bryce Matthew , Schunk Jeff E.
Published: January 2018

Objectives

We evaluated the association between the emergency department (ED) triage chief complaint and rate of missed appendicitis in children.

Methods

We performed a retrospective chart review of patients who presented to a pediatric ED and were diagnosed with appendicitis over 5 years (July 1, 2009 to June 30, 2014). We reviewed the medical record for any additional ED visits in the 7 days preceding the diagnosis of appendicitis. Triage chief complaints were classified as “suggestive of appendicitis” (abdominal pain, right lower quadrant pain, or rule out appendicitis) or “nonspecific” (fever, vomiting, dehydration, etc). We evaluated the association between triage chief complaint and missed diagnosis of appendicitis.

Results

We reviewed 1680 patients with appendicitis. In 67 (4%) cases, patients had at least 1 additional ED visit during the week preceding the diagnosis of appendicitis. When comparing those diagnosed with appendicitis at their initial ED visit to those diagnosed after multiple visits, we found no difference in age (9.9 vs 10.1 years, P = 0.665), sex (55.7% vs 49.3% male, P = 0.291), white blood cell count (14.4 vs 12.3 × 103/L, P = 0.115), or presence of fever (19.9% vs 19.4%, P = 0.920). Of patients with a triage chief complaint that was suggestive of appendicitis, 3.8% were missed on their initial ED visit versus 8.8% of those with a nonspecific triage chief complaint (odds ratio, 2.46; 95% confidence interval, 1.1–5.6).

Conclusions

A triage chief complaint less suggestive of appendicitis was associated with a higher rate of missed appendicitis in a pediatric ED. Our findings further confirm the potential impact of anchoring bias by a triage chief complaint when attempting to diagnose appendicitis.
Aspergillus and other respiratory fungal infections in the ICU: diagnosis and management
Authors: Paiva José-Artur , Mergulhão Paulo , Pereira José Manuel
Published: January 2018

Purpose of review

Filamentous fungi respiratory infections, namely because of Aspergillus, Mucorales, Fusarium, or Scedosporium, show rising incidence and occur more in populations which are not classically immunosuppressed. This and their persistent dismal prognosis are the focus of this review.

Recent findings

Both an early diagnosis, rooted on a high level of suspicion and based on clinical picture, radiology, cultural microbiological exams, fungal biomarkers, PCR and biopsy, and an early therapy, including immunorecovery, whenever possible, good antifungal selection, and surgery for source control, are paramount to maximize the outcome in these diseases. An evolving antifungal armamentarium and a more Pharmacokinetics/Pharmacodynamics-based antifungal prescription may help to improve the prognosis.

Improved awareness of these infections may increase the level of suspicion, promoting early diagnosis and treatment, ideally supported with expert stewardship.
Determining when to stop antiepileptic drug treatment
Authors: Schachter Steven C.
Published: January 2018

Purpose of review

As the number of patients diagnosed with epilepsy continues to rise and the pharmacological and device-based treatment options for epilepsy increase, determining when to stop antiepileptic drug (AED) treatment continues to be an important issue for patient management and counseling.

Recent findings

This review focuses on outcomes following AED withdrawal in seizure-free adults with epilepsy. Practical considerations are also discussed because, despite the importance of this topic, relatively little progress has been made in the past year regarding the identification of patients whose risk for recurrent seizures after AED withdrawal is no higher than that of the general population.

Although articles in the past year have updated the debates about whether and when to discontinue AEDs in seizure-free adults and have suggested potential utility for electroencephalograms as a prognostic tool for AED reduction as well as for an AED withdrawal risk calculator, decisions about AED withdrawal should still be based on the known risks and consequences of seizure recurrence and be made following well documented discussions between doctor and patient/carer.
ECT and Pronounced Impairment in Spatial Cognition
Authors: Andrade Chittaranjan , Prasad Yameni , Devaraj Aathira , Pinto Ekta Franscina , Shukla Lekhansh
Published: January 2018

Introduction

Electroconvulsive therapy (ECT) is associated with memory deficits on neuropsychological assessment. The association of ECT with nonmemory cognitive deficits has been poorly studied.

Methods

We present a 40-year-old woman who showed a bizarre form of spatial cognition impairment on a subtest of the Tactual Performance Test (TPT) after recovering from depression with 6 alternate day, thrice-weekly, inpatient ECT treatments. This woman was part of a naturalistic, nonblind study that examined nonmemory cognitive deficits in antidepressant-treated depressed patients who did and did not receive ECT.

Results

The impairment was in the form of bizarrely drawn reproductions of differently shaped wooden blocks that had been presented to the patient when she was blindfolded. The impairment was still evident when she was retested (3 hours later) under substantially simplified conditions but was much attenuated approximately 2.5 weeks later.

Conclusions

On the surface, it seems that ECT had induced severe impairment in spatial cognition and that the impairment showed the familiar pattern of attenuation with the passage of time. However, another recovered patient in the study, who did not receive ECT, also showed substantial spatial deficits on the same subtest of the TPT, and the attenuation of the deficits across time in the ECT-treated patient was probably a result of repeated exposure to the task. We suggest that not all patients who seem to experience spectacular cognitive impairment after ECT have deficits that are attributable to ECT.
Three-stage processing of category and variation information by entangled interactive mechanisms of peri-occipital and peri-frontal cortices
Authors: Karimi-Rouzbahani Hamid
Published: January 2018

Invariant object recognition, which refers to the ability of precisely and rapidly recognizing objects in the presence of variations, has been a central question in human vision research. The general consensus is that the ventral and dorsal visual streams are the major processing pathways which undertake category and variation encoding in entangled layers. This overlooks the mounting evidence which support the role of peri-frontal areas in category encoding. These recent studies, however, have left open several aspects of visual processing in peri-frontal areas including whether these areas contributed only in active tasks, whether they interacted with peri-occipital areas or processed information independently and differently. To address these concerns, a passive EEG paradigm was designed in which subjects viewed a set of variation-controlled object images. Using multivariate pattern analysis, noticeable category and variation information were observed in occipital, parietal, temporal and prefrontal areas, supporting their contribution to visual processing. Using task specificity indices, phase and Granger causality analyses, three distinct stages of processing were identified which revealed transfer of information between peri-frontal and peri-occipital areas suggesting their parallel and interactive processing of visual information. A brain-plausible computational model supported the possibility of parallel processing mechanisms in peri-occipital and peri-frontal areas. These findings, while advocating previous results on the role of prefrontal areas in object recognition, extend their contribution from active recognition, in which peri-frontal to peri-occipital feedback mechanisms are activated, to the general case of object and variation processing, which is an integral part of visual processing and play role even during passive viewing.
A temporally dynamic Foxp3 autoregulatory transcriptional circuit controls the effector Treg programme
Authors: Bending David , Paduraru Alina , Prieto Martin Paz , Crompton Tessa , Ono Masahiro
Published: January 2018

Regulatory T cells (Treg) are negative regulators of the immune response. Whilst thymic Treg generation is well studied, it is not known whether and how Foxp3 transcription is induced and regulated in the periphery during immune responses. Here we use Foxp3 Timer of cell kinetics and activity (Tocky) mice, which report real-time Foxp3 gene transcription by measuring the spontaneous maturation of Fluorescent Timer protein from Blue to Red fluorescence, to identify the flux of Foxp3-to Foxp3+ T cells within the periphery and analyse the real-time activity of Foxp3 transcription. Using a murine model of skin allergy, we show that both the flux of new Foxp3 expressors and the rate of Foxp3 transcription are increased at inflamed sites. These persistent dynamics of Foxp3 transcription determine the effector Treg programme, and are dependent on a Foxp3 autoregulatory transcriptional circuit, as evidenced by analysis of T cells lacking functional Foxp3 protein. Such reactive and persistent Foxp3 transcriptional activity controls the expression of coinhibitory molecules including CTLA-4 and effector-Treg signature genes. Using RNA-seq, we identify two groups of surface proteins based on their relationship to the temporal dynamics of Foxp3 transcription, and we show proof-of-principle for the manipulation of Foxp3 dynamics by immunotherapy: new Foxp3 flux is promoted by anti-TNFRII antibody, and high frequency Foxp3 expressors are depleted by anti-OX40 antibody. Collectively, our study dissects time-dependent mechanisms behind Foxp3-driven T cell regulation, and establishes the Foxp3-Tocky system as a tool to investigate the mechanisms behind T cell immunotherapies.
Functionally asymmetric motor neurons coordinate locomotion of Caenorhabditis elegans
Authors: Tolstenkov Oleg , Van der Auwera Petrus , Liewald Jana F. , Costa Wagner Steuer , Bazhanova Olga , Gemeinhard Tim , Bergs Amelie C. F. , Gottschalk Alexander
Published: January 2018

Invertebrate nervous systems are valuable models for fundamental principles of the control of behavior. Ventral nerve cord (VNC) motor neurons in Caenorhabditis elegans represent one of the best studied locomotor circuits, with known connectivity and functional information about most of the involved neuron classes. However, for one of those, the AS motor neurons (AS MNs), no physiological data is available. Combining specific expression and selective illumination, we precisely targeted AS MNs by optogenetics and addressed their role in the locomotion circuit. After photostimulation, AS MNs induce currents in post-synaptic body wall muscles (BWMs), exhibiting an initial asymmetry of excitatory output. This may facilitate complex regulatory motifs for adjusting direction during navigation. By behavioral and photo-inhibition experiments, we show that AS MNs contribute to propagation of the antero-posterior body wave during locomotion. By Ca2+-imaging in AS MNs and in their synaptic partners, we also reveal that AS MNs play a role in mediating forward and backward locomotion by integrating activity of premotor interneurons (PINs), as well as in coordination of the dorso-ventral body wave. AS MNs do not exhibit pacemaker properties, but potentially gate VNC central pattern generators (CPGs), as indicated by ceasing of locomotion when AS MNs are hyperpolarized. AS MNs provide positive feedback to the PIN AVA via gap junctions, a feature found also in other locomotion circuits. In sum, AS MNs have essential roles in coordinating locomotion, combining several functions, and emphasizing the compressed nature of the C. elegans nervous system in comparison to higher animals.

Highlights

A class of motor neurons with unidentified function – AS cholinergic motor neurons - was characterized in C. elegans.

AS neurons show asymmetry in both input and output and are specialized in coordination of dorso-ventral undulation bends.

AS neurons mediate antero-posterior propagation of the undulatory body wave during locomotion.

AS neurons integrate signals for forward and reverse locomotion from premotor interneurons and may gate ventral nerve cord central pattern generators (CPGs) via gap junctions.
TOGGLe, a flexible framework for easily building complex workflows and performing robust large-scale NGS analyses
Authors: Tranchant-Dubreuil Christine , Ravel Sébastien , Monat Cécile , Sarah Gautier , Diallo Abdoulaye , Helou Laura , Dereeper Alexis , Tando Ndomassi , Orjuela-Bouniol Julie , Sabot François
Published: January 2018

The advent of NGS has intensified the need for robust pipelines to perform high-performance automated analyses. The required softwares depend on the sequencing method used to produce raw data (e.g. Whole genome sequencing, Genotyping By Sequencing, RNASeq) as well as the kind of analyses to carry on (GWAS, population structure, differential expression). These tools have to be generic and scalable, and should meet the biologists needs.

Here, we present the new version of TOGGLe (Toolbox for Generic NGS Analyses), a simple and highly flexible framework to easily and quickly generate pipelines for large-scale second- and third-generation sequencing analyses, including multi-sample and multi-threading support. TOGGLe is a workflow manager designed to be as effortless as possible to use for biologists, so the focus can remain on the analyses. Pipelines are easily customizable and supported analyses are reproducible and shareable. TOGGLe is designed as a generic, adaptable and fast evolutive solution, and has been tested and used in large-scale projects on various organisms. It is freely available at http://toggle.southgreen.fr/, under the GNU GPLv3/CeCill-C licenses) and can be deployed onto HPC clusters as well as on local machines.
Easy Hi-C: A simple efficient protocol for 3D genome mapping in small cell populations
Authors: Lu Leina , Liu Xiaoxiao , Peng Jun , Li Yan , Jin Fulai
Published: January 2018

Despite the growing interest in studying the mammalian genome organization, it is still challenging to map the DNA contacts genome-wide. Here we present easy Hi-C (eHi-C), a highly efficient method for unbiased mapping of 3D genome architecture. The eHi-C protocol only involves a series of enzymatic reactions and maximizes the recovery of DNA products from proximity ligation. We show that eHi-C can be performed with 0.1 million cells and yields high quality libraries comparable to Hi-C.
Time-scale separation and stochasticity conspire to impact phenotypic dynamics in the canonical and inverted Bacillus subtilis core genetic regulation circuits
Authors: Hao Lijie , Yang Zhuoqin , Turcotte Marc
Published: January 2018

In this work, we study two seemingly unrelated aspects of core genetic nonlinear dynamical control of the competence phenotype in Bacillus subtilis, a common Gram-positive bacterium living in the soil. We focus on hitherto unchartered aspects of the dynamics by exploring the effect of time scale separation between transcription and translation and, as well, the effect of intrinsic molecular stochasticity. We consider these aspects of regulatory control as two possible evolutionary handles. Hence, using theory and computations, we study how the onset of oscillations breaks the excitability-based competence phenotype in two topologically close evolutionary competing circuits: the canonical “wild-type” regulation circuit selected by Evolution and, the indirect-feedback inverted circuit that failed to be selected by Evolution, as was shown elsewhere, due to dynamical reasons.
AGO CLIP reveals an activated network for acute regulation of brain glutamate homeostasis after ischemic stroke
Authors: Kobayashi Mariko , Benakis Corinne , Anderson Corey , Moore Michael J. , Poon Carrie , Uekawa Ken , Dyke Jonathan P. , Fak John J. , Mele Aldo , Park Christopher Y. , Zhou Ping , Anrather Josef , Iadecola Costantino , Darnell Robert B.
Published: January 2018

Post-transcriptional regulation by miRNAs is essential for complex molecular responses to physiological insult and disease. Although many disease-associated miRNAs are known, their global targets and culminating network effects on pathophysiology remain poorly understood. We applied AGO CLIP to systematically elucidate altered miRNA-target interactions in brain following ischemia/reperfusion (I/R) injury. Among 1,190 identified, most prominent was the cumulative loss of target regulation by miR-29 family members. Integration of translational and time-course RNA profiles revealed a dynamic mode of miR-29 target de-regulation, led by acute translational activation and later increase in RNA levels, allowing rapid proteomic changes to take effect. These functional regulatory events rely on canonical and non-canonical miR-29 binding and engage glutamate reuptake signals to control local glutamate levels. These results uncover a miRNA target network that acts acutely to maintain brain homeostasis after ischemic stroke.
Causal Discovery of Feedback Networks with Functional Magnetic Resonance Imaging
Authors: Sanchez-Romero R , Ramsey J.D. , Zhang K. , Glymour M. R. K , Huang B , Glymour C.
Published: January 2018

We test the adequacies of several proposed and two new statistical methods for recovering the causal structure of systems with feedback that generate noisy time series closely matching real BOLD time series. We compare: an adaptation for time series of the first correct method for recovering the structure of cyclic linear systems; multivariate Granger causal regression; the GIMME algorithm; the Ramsey et al. non-Gaussian methods; two non-Gaussian methods proposed by Hyv¨arinen and Smith; a method due to Patel, et al.; and the GlobalMIT algorithm. We introduce and also compare two new methods, the Fast Adjacency Skewness (FASK) and Two-Step, which exploit non-Gaussian features of the BOLD signal in different ways. We give theoretical justifications for the latter two algorithms. Our test models include feedback structures with and without direct feedback (2-cycles), excitatory and inhibitory feedback, models using experimentally determined structural connectivities of macaques, and empirical resting state and task data. We find that averaged over all of our simulations, including those with 2-cycles, several of these methods have a better than 80% orientation precision (i.e., the probability a directed edge is in the true generating structure given that a procedure estimates it to be so) and the two new methods also have better than 80% recall (probability of recovering an orientation in the data generating model). Recovering inhibitory direct feedback loops between two regions is especially challenging.
Action-outcome knowledge dissociates from behavior in obsessive-compulsive disorder following contingency degradation
Authors: Vaghi Matilde M. , Cardinal Rudolf N. , Apergis-Schoute Annemieke M. , Fineberg Naomi A. , Sule Akeem , Robbins Trevor W.
Published: January 2018

Goal-directed and habitual systems orchestrate action control. In disorders of compulsivity, their interplay seems disrupted and actions persist despite being inappropriate and without relationship to the overall goal. We manipulated action–outcome contingency to test whether actions are goal-directed or habitual in obsessive-compulsive disorder (OCD), the prototypical disorder of compulsivity, in which prominent theories have suggested that dysfunctional beliefs underlie the necessity for compulsive actions.

OCD patients responded more than controls when an action was causally less related to obtaining an outcome, indicating excessive habitual responding. Patients showed intact explicit action–outcome knowledge but this was not translated normally into behavior; the relationship between causality judgment and responding was blunted. OCD patients’ actions were dissociated from explicit action-outcome knowledge, providing experimental support for the ego-dystonic nature of OCD and suggesting that habitual action is not sustained by dysfunctional belief.
No Evidence for Systematic White Matter Correlates of Dyslexia: An Activation Likelihood Estimation Meta-Analysis
Authors: Moreau David , Stonyer Josephine E. , McKay Nicole S. , Waldie Karen E.
Published: January 2018

Dyslexia is a prevalent neurodevelopmental disorder, characterized by reading and spelling difficulties. Beyond the behavioral and functional correlates of this condition, a growing number of studies have explored structural differences between individuals with dyslexia and typically developing individuals. To date, findings remain disparate – some studies suggest differences in fractional anisotropy (FA), an indirect measure of white matter integrity, whereas others do not identify significant disparities. Here, we synthesized the existing literature on this topic by conducting a meta-analysis of Diffusion Tensor Imaging (DTI) studies investigating white matter correlates of dyslexia via voxel-based analyses (VBA) of FA. Our results showed no reliable clusters underlying differences between dyslexics and typical individuals, after correcting for multiple comparisons (false discovery rate correction). Because group comparisons might be too coarse to yield subtle differences, we further explored differences in FA as a function of reading ability, measured on a continuous scale. Consistent with our initial findings, reading ability was not associated with reliable differences in white matter integrity. These findings nuance the current view of profound, structural differences underlying reading ability and its associated disorders, and suggest that their neural correlates might be more subtle than previously thought.
Green function of correlated genes and the mechanical evolution of protein
Authors: Dutta Sandipan , Eckmann Jean-Pierre , Libchaber Albert , Tlusty Tsvi
Published: January 2018

There has been growing evidence that cooperative interactions and configurational rearrangements underpin protein functions. But in spite of vast genetic and structural data, the information-dense, heterogeneous nature of protein has held back the progress in understanding the underlying principles. Here we outline a general theory of protein that quantitatively links sequence, dynamics and function: The protein is a strongly-coupled amino acid network whose interactions and large-scale motions are captured by the mechanical propagator, also known as the Green function. The propagator relates the gene to the connectivity of the amino acid network and the transmission of forces through the protein. How well the force pattern conforms to the collective modes of the functional protein is measured by the fitness. Mutations introduce localized perturbations to the propagator which scatter the force field. The emergence of function is manifested by a topological transition when a band of such perturbations divides the protein into subdomains. Epistasis quantifies how much the combined effect of multiple mutations departs from additivity. We find that epistasis is the nonlinearity of the Green function, which corresponds to a sum over multiple scattering paths passing through the localized perturbations. We apply this mechanical framework to the simulations of protein evolution, and observe long-range epistasis which facilitates collective functional modes. Our model lays the foundation for understanding the protein as an evolved state of matter and may be a prototype for other strongly-correlated living systems.
GtTR: Bayesian estimation of absolute tandem repeat copy number using sequence capture and high throughput sequencing
Authors: Ganesamoorthy Devika , Cao Minh Duc , Duarte Tania , Chen Wenhan , Coin Lachlan
Published: January 2018

Background

Tandem repeats comprise significant proportion of the human genome including coding and regulatory regions. They are highly prone to repeat number variation and nucleotide mutation due to their repetitive and unstable nature, making them a major source of genomic variation between individuals. Despite recent advances in high throughput sequencing, analysis of tandem repeats in the context of complex diseases is still hindered by technical limitations.

Methods

We report a novel targeted sequencing approach, which allows simultaneous analysis of hundreds of repeats. We developed a Bayesian algorithm, namely – GtTR - which combines information from a reference long-read dataset with a short read counting approach to genotype tandem repeats at population scale. PCR sizing analysis was used for validation.

Results

We used a PacBio long-read sequenced sample to generate a reference tandem repeat genotype dataset with on average 13% absolute deviation from PCR sizing results. Using this reference dataset GtTR generated estimates of VNTR copy number with accuracy within 95% high posterior density (HPD) intervals of 68% and 83% for capture sequence data and 200X WGS data respectively, improving to 87% and 94% with use of a PCR reference. We show that the genotype resolution increases as a function of depth, such that the median 95% HPD interval lies within 25%, 14%, 12% and 8% of the its midpoint copy number value for 30X, 200X WGS, 395X and 800X capture sequence data respectively. We validated nine targets by PCR sizing analysis and genotype estimates from sequencing results correlated well with PCR results.

Conclusions

The novel genotyping approach described here presents a new cost-effective method to explore previously unrecognized class of repeat variation in GWAS studies of complex diseases at the population level. Further improvements in accuracy can be obtained by improving accuracy of the reference dataset.
Using paired serology and surveillance data to quantify dengue transmission and control during a large outbreak in Fiji
Authors: Kucharski Adam J , Kama Mike , Watson Conall H , Aubry Maite , Funk Sebastian , Henderson Alasdair D , Brady Oliver J , Vanhomwegen Jessica , Manuguerra Jean-Claude , Lau Colleen L , Edmunds W John , Aaskov John , Nilles Eric J , Cao-Lormeau Van-Mai , Hue Stephane , Hibberd Martin
Published: January 2018

Dengue is a major health burden, but it can be challenging to examine transmission dynamics and evaluate control measures because outbreaks depend on multiple factors, including human population structure, prior immunity and climate. We combined population-representative paired sera collected before and after the major 2013/14 dengue-3 outbreak in Fiji with surveillance data to determine how such factors influence dengue virus transmission and control in island settings. Our results suggested the 10-19 year-old age group had the highest risk of acquiring infection, but we did not find strong evidence that other demographic or environmental risk factors were linked to seroconversion. Mathematical modelling showed that temperature-driven variation in transmission and herd immunity could not fully explain observed dynamics. However, there was evidence of an additional reduction in transmission coinciding with a vector clean-up campaign, which may have contributed to the decline in cases and prevented transmission continuing into the following season.
Edge Factors: Scientific Frontier Positions of Nations
Authors: Packalen Mikko
Published: January 2018

A key decision in scientific work is whether to build on novel or well-established ideas. Because exploiting new ideas is often harder than more conventional science, novel work can be especially dependent on interactions with colleagues, the training environment, and ready access to potential collaborators. Location may thus influence the tendency to pursue work that is close to the edge of the scientific frontier in the sense that it builds on recent ideas. We calculate for each nation its position relative to the edge of the scientific frontier by measuring its propensity to build on relatively new ideas in biomedical research. Text analysis of 20+ million publications shows that the United States and South Korea have the highest tendencies for novel science. China has become a leader in favoring newer ideas when working with basic science ideas and research tools, but is still slow to adopt new clinical ideas. Many locations remain far behind the leaders in terms of their tendency to work with novel ideas, indicating that the world is far from flat in this regard.
Improving new product development (NPD) process by analyzing failure cases
Authors: Kim Yeon-Hak , Park Sun-Woong , Sawng Yeong-Wha
Published: January 2018

Purpose

The purpose of this study is to develop an appropriate new product development (NPD) process of Company “T”, a medium-sized firm, by analyzing the existing NPD process and failure cases of the Company.

Design/methodology/approach

The proposed research framework is as follows: first, prospective studies of the NPD process are performed using the existing literature and preliminary references; second, comparative analysis between the current processes and a NPD process is performed; third, phase-based evaluations upon failed product cases are conducted with a NPD process so as to identify the abridged steps and root-causes of failures; finally, renewed priorities are set forth by utilizing the analytic hierarchy process analysis and questionnaire analysis upon the above identified causes of failures.

Findings

The resulting accomplishments include the establishment of NPD processes that resonates with the current states of Company “T”, which, in turn, ensures the increase of efficiency, the decrease in development duration and the strategy of capacity-concentration and priority-selection.

Originality/value

As Company “T”’s development process is outdated and products are developed without adequate market information research and feasibility analysis, the percentage of failed development project is as high as 87 per cent. Thus, this study aims to develop an appropriate NPD process of Company “T” by analyzing the existing NPD process and failure cases of the Company.
Creating ventures: decision factors in new venture creation
Authors: Kirkley William W.
Published: January 2018

Purpose

The purpose of this pilot study was to identify the key factors that influence the decisions of entrepreneurs who are considering the creation of a new venture. The pilot was conducted to explore the cognitive antecedents of entrepreneurial decision-making and whether specific factors contribute to the decision to create a new venture.

Design/methodology/approach

The study utilised an inductive and interpretive research design within a constructivist paradigm. The sample comprised entrepreneurs situated in a business incubation unit who engaged in a series of semi-structured interviews. The results of this study will be used to refine the questions asked in preparation for a larger sample using in-depth interviews with identified entrepreneurs. The resulting narrative in this pilot was subjected to discourse analysis and is categorised into relevant themes.

Findings

The findings in this pilot study reveal that factors such as technological advancement, market opportunity, competition, customer demand and prevailing market conditions have a significant influence on the decision-making process involved in creating a new venture.

Research limitations/implications

Although the pilot has identified several factors in entrepreneurial decision-making, further work will be needed in the research design to be able to expose the cognitive processes associated with each factor. The aim is to identify the common cognitive characteristics associated with thinking through the decision to create a new venture with a much larger sample of entrepreneurs.

Originality/value

The value of this research lies in exploring and developing a better understanding of the antecedent cognitive processes used by entrepreneurs for identifying unique, innovative new ideas and converting them into exploitable products or services through new venture creation.