bluuebunny/crossref_metadata_2025 huggingface dataset:
Attention-Deficit Hyperactivity Disorder Risk: Interaction Between Parental Age and Maternal History of Attention-Deficit Hyperactivity Disorder
Authors: Wang Xinhui , Martinez Mayra P. , Chow Ting , Walthall Johanna C. , Guber Kevin M. , Xiang Anny H.
Published: May 2019

Objective:

To assess the interaction between maternal attention-deficit/hyperactivity disorder (ADHD) history and young parental age on child's ADHD risk.

Methods:

The study included 321,272 singleton children born between 1995 and 2012 from hospitals within a single integrated health care organization. The children were prospectively followed up through electronic medical record systems from birth until the first date of the following: date of clinical diagnosis of ADHD, last date of continuous health plan membership, death due to any cause, or December 31, 2017. Risks of ADHD associated with a maternal history of ADHD before pregnancy and young parental age were assessed by using Cox regression adjusting for potential confounders.

Results:

The children were followed up for a median (interquartile range) of 8.9 (6.2, 13.6) years from birth. Among them, 5.1% had ADHD diagnosis, 1.8% had a maternal history of ADHD before the pregnancy, and 4.4% had mothers <20 years and 2.3% had fathers <20 years at date of birth. The hazard ratio (HR) of ADHD in children associated with parental age <20 years varied by maternal history of ADHD (p < 0.005 for both multiplicative and additive interactions). For children without a maternal history of ADHD, the HR associated with at least 1 parent <20 years was 1.14 (95% confidence interval 1.04–1.24). However, for children with a maternal history of ADHD, the HR associated with at least 1 parent <20 years was 1.92 (95% confidence interval 1.31–2.82).

Conclusion:

High ADHD risk in offspring associated with young parenthood was predominantly observed among children with a maternal history of ADHD.
Stimulation and Early Child Development in China: Caregiving at Arm's Length
Authors: Yue Ai , Shi Yaojiang , Luo Renfu , Wang Boya , Weber Ann , Medina Alexis , Kotb Sarah , Rozelle Scott
Published: May 2019

Objective:

To provide an empirical overview of the parenting landscape in rural China, focusing on 18- to 30-month-old children and their caregivers in rural Shaanxi province.

Methods:

We collected unique data on 1442 caregiver-toddler dyads in rural areas of Shaanxi province and examined caregiver attitudes toward parenting, sources of information about parenting, and interactive parenting practices, and how each of these differed across generations. We measured how parenting attitudes and sources of information informed parenting practices. Finally, we measured levels of child development in our sample and the association between parenting practices and children's developmental outcomes.

Results:

Most of the caregivers did not engage with children in a way that encouraged early development. Caregivers rarely told stories, sang, or used toys to play with their children. Grandmothers were more stressed by the children in their care and engaged significantly less than mothers did in the 3 stimulating interactions. Professional sources of information about parenting were underutilized by all caregivers. We found high rates of developmental delay in our sample and showed that these delays were associated with the lack of caregiver engagement.

Conclusion:

Our findings suggest that the major economic and social shifts occurring in rural China have not led to a widespread prevalence of stimulative parenting practices. Although caregivers report positive attitudes toward child-rearing, reliable sources of scientific information are lacking. Our results show a troubling generational disconnect between the information-seeking behaviors and parenting practices of rural caregivers.
Changes in Endothelial Cell Count Up to Three Years After Implantation of Toric Implantable Collamer Lenses
Authors: Bohac Maja , Jagic Mateja , Biscevic Alma , Shijakova Violeta , Gabric Nikica , Patel Sudi
Published: May 2019

Purpose:

To determine the temporal effect of toric implantable collamer lens (TICL) implantation and location on corneal endothelial cell density (ECD) over a period of 36 months after surgery.

Methods:

ECD [number of cells per square millimeter estimated using the Specular Microscope SP-1P (Topcon Europe Medical B.V., Netherlands)] data were collected from cases deemed suitable for the TICL (VTICMO, VTICM5; STAAR Surgical, Nidau, Switzerland). The preoperative refractive error (sphere and cylinder) ranged from −1.00 to −22.25 diopter sphere and from −0.50 to −5.50 diopter cylinder. ECD was evaluated at preoperative and all postoperative sessions.

Results:

Key findings were as follows: the mean ECD (±SD, 95% confidence interval) was 2720 cells/mm2 (±272, 2620–2820 cells/mm2) preoperatively, which was reduced to 2372 cells/mm2 (±325, 2250–2490 cells/mm2) at 36 months postoperatively (P < 0.001). Linear regression revealed the following significant correlations between the (1) log of the change in ECD (y1) and log of preoperative ECD (x1) at 2 years postoperatively, y1 = 2.513x1−6.2816 (n = 62, r= 0.3503, P = 0.005); (2) mean ECD (y2) and log time (in months, x2), y2= 2543.7−36.997x2−38.99x2
2 (r=−0.9654, n = 7, P = 0.0004); and (3) mean axial distance between the front surface of the crystalline lens and the TICL back surface (y3) and time postoperatively (in months, x3), y3 = 0.1035x3
2−5.2808x3 +473.18 (r = 0.8512, n = 7, P = 0.015).

Conclusions:

Expected ECD loss after TICL implantation by 2 years postoperatively is predictable. On average, over 3 years after implantation, there is (1) an initial rapid decline in ECD, followed by a gradual fall in the rate of cell loss, and (2) a gradual fall in the distance between the TICL and the crystalline lens by 2 years postoperatively, followed by a reversal by the third year.
Infliximab Therapy and the Central Nervous Demyelination in Patients with Kawasaki Disease
Authors: Sagara Yuka , Muneuchi Jun , Shimabukuro Wataru , Joo Masahiko , Yoshino Miwa , Nakamura Ryoko , Yoneda Toru , Sugitani Yuichiro , Watanabe Mamie , Mizushima Akira , Takahashi Yasuhiko
Published: May 2019

We performed brain magnetic resonance imaging in 14 patients with Kawasaki disease who were treated with infliximab (IFX) at 56 months of age (32–62 months of age) and 23 months (5–35 months) after IFX therapy. Magnetic resonance imaging showed no finding of the central nervous demyelination. IFX therapy is not related to central nervous demyelination in patients with Kawasaki disease.
Machine-learned analysis of the association of next-generation sequencing–based genotypes with persistent pain after breast cancer surgery
Authors: Kringel Dario , Kaunisto Mari A. , Kalso Eija , Lötsch Jörn
Published: May 2019

Cancer and its surgical treatment are among the most important triggering events for persistent pain, but additional factors need to be present for the clinical manifestation, such as variants in pain-relevant genes. In a cohort of 140 women undergoing breast cancer surgery, assigned based on a 3-year follow-up to either a persistent or nonpersistent pain phenotype, next-generation sequencing was performed for 77 genes selected for known functional involvement in persistent pain. Applying machine-learning and item categorization techniques, 21 variants in 13 different genes were found to be relevant to the assignment of a patient to either the persistent pain or the nonpersistent pain phenotype group. In descending order of importance for correct group assignment, the relevant genes comprised DRD1, FAAH, GCH1, GPR132, OPRM1, DRD3, RELN, GABRA5, NF1, COMT, TRPA1, ABHD6, and DRD4, of which one in the DRD4 gene was a novel discovery. Particularly relevant variants were found in the DRD1 and GPR132 genes, or in a cis-eCTL position of the OPRM1 gene. Supervised machine-learning–based classifiers, trained with 2/3 of the data, identified the correct pain phenotype group in the remaining 1/3 of the patients at accuracies and areas under the receiver operator characteristic curves of 65% to 72%. When using conservative classical statistical approaches, none of the variants passed α-corrected testing. The present data analysis approach, using machine learning and training artificial intelligences, provided biologically plausible results and outperformed classical approaches to genotype–phenotype association.
Ambulatory Iodopovidone Instillation Via Indwelling Pleural Catheters For Malignant Pleural Effusions
Authors: Matus Ismael , Ho Patrick
Published: May 2019

Malignant pleural effusions’ (MPEs) treatment goals focus on optimizing the quality of life and decreasing time spent in health care facilities in this patient population with limited life expectancy. Numerous pleural palliation options and combination of these exist and continue to undergo studies to identify safe, superior and ideally patient-centered care. We report a cohort of 13 patients with symptomatic MPE managed with iodopovidone intrapleural instillation via an indwelling pleural catheter (IPC) in the ambulatory setting. Successful complete pleurodesis was achieved in 10 of 13 (76.9%) patients at a median time of 5 days with IPC removal at a median of 16 days. Two patient obtained partial pleurodesis with IPC removal, 1 required IPC reinsertion due to symptom recurrence. Complications were limited to intraprocedural pain in 4 patients (31%). Iodopovidone pleurodesis via IPC may represent a safe, feasible, and effective ambulatory-based option for pleural palliation in MPE.
Early Detection of Pump Thrombosis in Patients With Left Ventricular Assist Device
Authors: Grabska Joanna , Schlöglhofer Thomas , Gross Christoph , Maw Martin , Dimitrov Kamen , Wiedemann Dominik , Zimpfer Daniel , Schima Heinrich , Moscato Francesco
Published: May 2019

Pump thrombosis (PT) is a serious adverse event in patients receiving left ventricular assist devices (LVAD). The study aims to determine whether pump parameters and clinical data may enable early detection of PT. This retrospective study included 88 patients who received an LVAD between 2012 and 2015 among which those with intra-PT were identified. In a propensity score–matched control group observation, time periods were matched with time before thrombosis. International normalized ratio (INR) time in therapeutic range (TTR) and lactate dehydrogenase (LDH) were analyzed for 60 days preceding PT. Furthermore, pump data (power, flow, and speed) in HeartWare ventricular assist devices (HVAD) patients were analyzed 7 days before PT using a mixed-design analysis of variance to investigate temporal changes in pump data. Pump thrombosis occurred in 15 patients (13 males, age 58 ± 10 years, 7 HeartMate II and 8 HVAD). International normalized ratio therapeutic range (2.0–3.0) and acetylsalicylic acid daily doses (100–200 mg) were similar for both groups, but patients with PT had lower TTR (36% vs. 65%; p = 0.025). No significant difference in LVAD power between groups was seen at baseline (p = 0.31), and power did not change in the control group over time (p > 0.99). Lactate dehydrogenase increased already 1 week prior PT and power from 4.4 ± 0.8 W at baseline to 4.9 ± 0.8 W (p = 0.007) 2 days before readmission and to 6.5 ± 1.8 W (p = 0.015) at readmission. Pump thrombosis is associated with a lower percentage of INR TTR and elevated LDH before the event. A better monitoring of pump parameters would enable PT detection already up to 2 days in advance.
A Review of New and Emerging Techniques For Optical Diagnosis of Colonic Polyps
Authors: Glover Ben , Teare Julian , Patel Nisha
Published: May 2019

Background and aims:

Endoscopic imaging is a rapidly progressing field and benefits from miniaturization of advanced imaging technologies, which may allow accurate real-time characterization of lesions. The concept of the “optical biopsy” to predict polyp histology has gained prominence in recent years and may become clinically applicable with the advent of new imaging technology. This review aims to discuss current evidence and examine the emerging technologies as applied to the optical diagnosis of colorectal polyps.

Methods:

A structured literature search and review has been carried out of the evidence for diagnostic accuracy of image-enhanced endoscopy and emerging endoscopic imaging technologies. The image-enhanced endoscopy techniques are reviewed, including their basic scientific principles and current evidence for effectiveness. These include the established image-enhancement technologies such as narrow-band imaging, i-scan, and Fuji intelligent chromoendoscopy. More recent technologies including optical enhancement, blue laser imaging, and linked color imaging are discussed. Adjunctive imaging techniques in current clinical use are discussed, such as autofluorescence imaging and endocytoscopy. The emerging advanced imaging techniques are reviewed, including confocal laser endomicroscopy, optical coherence tomography, and Raman spectroscopy.

Conclusions:

Large studies of the established image-enhancement techniques show some role for the optical diagnosis of polyp histology, although results have been mixed, and at present only the technique of narrow-band imaging is appropriate for the diagnosis of low-risk polyps when used by an expert operator. Other image-enhancement techniques will require further study to validate their accuracy but show potential to support the use of a “resect-and-discard” approach to low-risk polyps. New technologies show exciting potential for real-time diagnosis, but further clinical studies in humans have yet to be performed.
Years of Life and Productivity Loss Because of Adult Sudden Unexpected Death in the United States
Authors: Mirzaei Mojtaba , Joodi Golsa , Bogle Brittany , Chen Sarah , Simpson Ross J.
Published: May 2019

Background:

Few studies have evaluated the years of life lost (YLL) and productivity loss due to sudden unexpected death (SUD). The burden of SUD on society is undetermined because of lack of population-based studies and comprehensive adjudication methods.

Objective:

We estimated YLL and productivity loss from SUD in working-age adults and compared it with the leading causes of death in the United States.

Methods:

We screened all out of hospital deaths among people aged 20–64 in Wake County, NC from 2013 to 2015 to adjudicate SUDs. We extrapolated Wake County incidence to estimate the age-standardized and sex-standardized rate of SUD in the United States. YLL was calculated based on the remaining life expectancy of the victims. Incorporating market and housekeeping value estimated the present value of lifetime productivity loss because of SUD.

Results:

SUD incidence rates in the US adults aged 20–64 were 49.3 (95% confidence interval, 41.2–58.3) and 21.7 (95% confidence interval, 16.5–27.8) per 100,000 among men and women, respectively. SUD resulted in the loss of 2 million years of life, accounting for 10.0% of YLL from all causes of death. Among natural causes of death, YLL from SUD was only lower than that from all cancers combined and heart disease. Lifetime productivity loss because of SUD was ~$51 billion, exceeding productivity loss from any individual cancer.

Conclusion:

SUD is an important source of YLL and productivity loss among adults aged 20–64. Such a high burden on society justifies prioritizing health policies and interventions toward preventing SUD.
Impact of Behavioral Feeding Intervention on Child Emotional and Behavioral Functioning, Parenting Stress, and Parent‐Child Attachment
Authors: Knight Rachel M. , Albright Jeremy J. , Huth‐Bocks Alissa , Morris Natalie K. , Mills Lauren , Klok Kaylin , Kallabat Nora , Drayton Amy K.
Published: May 2019

Objectives:

Behavioral intervention is the only treatment for pediatric feeding problems with well documented empirical support. However, parents may be hesitant to pursue behavioral intervention because of concerns about possible negative side effects on child behavioral health and the parent‐child relationship. This study investigated associations between behavioral feeding treatment and parenting stress, internalizing and externalizing behavior problems in young children, and parent‐child attachment quality.

Methods:

Participants included 16 mother‐child dyads seeking treatment from a behavioral feeding clinic at a large Midwestern university medical center. Children were between the ages of 30 and 45 months (adjusted) at baseline. Caregivers completed the Child Behavior Checklist for ages 1.5 to 5 (CBCL/1.5–5), the Parenting Stress Index, 3rd Edition Short Form (PSI/SF), and mother‐child dyads participated in the Strange Situation procedure at baseline and again after 6 months. The treatment group (n = 12) began outpatient behavioral feeding intervention following the baseline evaluation, whereas the control group (n = 12) remained on the clinic waitlist until after the 6‐month follow‐up.

Results:

The treatment group demonstrated decreases in internalizing and externalizing child behavior problems and parenting stress compared with the control group. No significant differences were demonstrated in parent‐child attachment quality within or between groups.

Conclusions:

Behavioral feeding intervention had positive effects on perceptions of child emotional and behavioral functioning and maternal parenting stress. Intervention also did not impact the quality of the mother‐child attachment relationship. Further research with a larger sample size and additional observational measures of behavior is needed to support the replicability and generalizability of these results.
Autopsy Observation as Experiential Learning for Nurse Practitioner Students in an Online Advanced Pathophysiology Course
Authors: Keiser Megan M. , Murray-Wright Margaret
Published: May 2019

Background

Many instructional classrooms now exist in the online environment, where it is difficult to integrate experiential teaching strategies. Autopsy-based education has been shown to be a valuable teaching tool for pathophysiology in a medical school curriculum.

Problem

There is a gap in the literature about the use of an autopsy observation in nurse practitioner (NP) education.

Approach

The purpose of this project was to develop and evaluate the effectiveness of an autopsy experience for NP students in an online advanced pathophysiology course.

Outcomes

Based on a review of course evaluations and reflective essays, the majority of students found this to be a valuable learning experience. The main barrier was locating a facility and scheduling the autopsy observation.

Conclusion

The benefits outweigh the barriers to providing experiential learning with an autopsy observation in an online pathophysiology course. As such, it should be considered in similar course offerings.
The prevalence of fracture extension in displaced femoral neck fractures in the elderly
Authors: Natsuhara Kyle Matsuo , Boutin Robert Downey , Lee Mark Andrew , Meehan John Patrick
Published: May 2019

Objective:

Arthroplasty is the common treatment for intracapsular femoral neck fractures in the elderly. Recent studies have shown that there may be more overall complications related to uncemented hemiarthroplasty compared to cemented, including more subsidence, intraoperative fractures, and postoperative fractures. Uncemented femoral components rely on a press fit, and the risk of these complications would be expected to increase in patients with unrecognized distal extension of femoral neck fractures. The purpose of this study is to determine the frequency of fracture extension of displaced femoral neck fractures in the elderly population.

Methods:

The electronic medical record database at our institution was retrospectively reviewed to search for consecutive reports from 2005 to 2015 of patients 65 years or older that sustained an intracapsular femoral neck fracture who had computed tomography (CT) examinations of the injury. Exclusion criteria were CTs that were not fine cut (<1.5 mm cuts) or occult femoral neck fractures that were seen only on magnetic resonance imaging. This resulted in 60 patients that were included in the study. Within this subset of patients, the CT scans were reassessed to look for extension of the fracture beyond the boundaries of the femoral neck. Of particular interest, were fracture lines that extended distal to the femoral neck, since these have the potential to affect the fit of an uncemented femoral stem. Data on subject age, gender, body mass index (BMI), and bone mineral density (BMD) were also collected, and it was determined if these demographics were predictive in patients having fracture extension. Treatment and follow-up data were collected for the patients as well.

Results:

Seven of 60 patients were identified to have fracture extension of intracapsular femoral neck fractures. The frequency of fracture extension of intracapsular femoral neck fractures distal to the femoral neck was 8.3% (5/60). All cases of fracture extension were nondisplaced or minimally displaced. 60% (3/5) of the distal fracture extensions were not diagnosed preoperatively by the radiologists or the treating orthopaedic surgeons. There was not a statistically significant difference when comparing age, gender, BMI, or BMD of the population group with distal fracture extension to that of the rest of the patient cohort.

Conclusions:

To our knowledge, this is the first study to report the frequency of fracture extension of displaced femoral neck fractures in the elderly population. The 8.3% rate of distal fracture extension in elderly femoral neck fractures may help explain the higher rate of subsidence, postoperative fracture and intraoperative fracture when applying uncemented hemiarthroplasty compared to cemented arthroplasty. It is important to be aware of the potential for this phenomenon.
Increased risk of deep venous thrombosis in patients with poor ankle dorsiflexion after lower limb immobilization
Authors: Aufwerber Susanna , Praxitelous Praxitelis , Edman Gunnar , Silbernagel Karin Grävare , Ackermann Paul W.
Published: May 2019

Objective:

Many trauma patients are at risk of pulmonary embolism due to unrecognized deep vein thrombosis (DVT). Restricted ankle dorsiflexion (AD) range of motion during leg immobilization is known to cause reduced venous blood flow. The aim of the present study was to assess whether AD at plaster cast removal is related to the incidence of DVT and to patient outcome.

Design:

Prospective observational cohort study.

Setting:

Level 1 Trauma Center.

Patients:

A total of 124 patients (97 men, 27 women; mean age 40.3 years) with plaster cast leg immobilization after surgical repair of Achilles tendon rupture were assessed.

Main outcome measures:

At 2 weeks postoperatively, assessments of AD and the incidence of DVT using compression duplex ultrasound were performed with observers blinded to patient grouping. Patients were dichotomized into 2 groups; poor or good AD, according to the mean AD, −7°. At 3- and 12 months patient-reported outcome was examined using validated questionnaires (ATRS and FAOS), and functional outcome using the heel-rise test.

Results:

Patients with poor AD sustained 42% DVTs, while patients with good AD exhibited a DVT-rate of 23% (P = .036). Logistic regression analysis corroborated this finding (OR = 2.62, P = .036; 95% CI = 1.06–6.44). AD was not linked to any long-term functional or patient-reported outcome.

Conclusions:

Reduced AD after plaster cast removal is associated with a higher risk of DVT. The results of this observational study warrant further prospective studies to confirm the effects of ankle dorsiflexion on the risk of developing venous thromboses.

Level of evidence: II
Cognitive Trajectory Phenotypes in Human Immunodeficiency Virus–Infected Patients
Authors: Dastgheyb Raha M. , Sacktor Ned , Franklin Donald , Letendre Scott , Marcotte Thomas , Heaton Robert , Grant Igor , McArthur Justin C. , Rubin Leah H. , Haughey Norman J.
Published: May 2019

Objective:

The presentation of cognitive impairments in HIV-infected individuals has transformed since the introduction of antiretroviral therapies. Although the overall prevalence of cognitive impairments has not changed considerably, frank dementia is now infrequent, and milder forms of cognitive impairments predominate. Mechanistic insights to the underlying causes of these residual cognitive impairments have been elusive, in part due to the heterogenous etiology of cognitive dysfunction in this population. Here, we sought to categorize longitudinal change in HIV-infected patients based on the performance in specific cognitive domains.

Design:

This study consisted of 193 participants from the CHARTER cohort with detailed demographic, clinical, and neuropsychological testing data obtained from 2 study visits interspersed by ∼6 months. Cognitive testing assessed executive function, learning and delayed recall, working memory, verbal fluency, speed of information processing, and motor skills. Change scores were calculated for each domain between the 2 study visits. Dimension reduction and clustering was accomplished by principal component analysis of change scores and k-means clustering to identify cognitive domains that group together and groups of subjects with similar patterns of change.

Results:

We identified 4 distinct cognitive change phenotypes that included declines in: (1) verbal fluency, (2) executive function (3) learning and recall, and (4) motor function, with approximately equal numbers of participants in each phenotype.

Conclusions:

Each of the 4 cognitive change phenotypes identify deficits that imply perturbations in specific neural networks. Future studies will need to validate if cognitive change phenotypes are associated with alterations in associated neural pathways.
Structured Reporting in Ultrasound
Authors: O'Connor Stacy D. , Kulkarni Naveen M. , Griffin Michael O. , Baruah Dhiraj , Sudakoff Gary S. , Tolat Parag P.
Published: May 2019

Structured reporting of ultrasound examinations can add value throughout the imaging chain. Reports may be created in a more efficient manner, with increased accuracy and clarity. Communication with referring providers and patients may be improved. Patient care can be enhanced through improved adherence with guidelines and local best practices. Radiology departments may benefit from improved billing and quality reporting. Consistent discrete data can enable research and collaborations between institutions. This article will review the multifaceted impact of structuring ultrasound reports.
Applications of Bone Morphogenetic Protein-2: Alternative Therapies in Craniofacial Reconstruction
Authors: Fisher Mark , Yee Kristen , Alba Brandon , Tanna Neil , Bastidas Nicholas , Bradley James P.
Published: May 2019

Large defects of the craniofacial skeleton can be exceedingly difficult to reconstruct since autologous bone grafts are limited by donor site morbidity and alloplastic implants have low biocompatibility. Bone morphogenetic proteins (BMPs) in craniofacial reconstruction have been used with mixed outcomes and complication concerns; however, results for specific indications have been promising.

In alveolar clefts, cranial vault defects, mandibular defects, and rare Tessier craniofacial clefts, BMP-2 impregnated in collagen matrix was looked at as an alternative therapy for challenging cases. In cases where structural support was required, BMP-2 was used as part of a construct with bio-resorbable plates. Demineralized bone was added in certain cases.

The authors described specific indications, detailed surgical techniques, and a review of the current literature regarding the use of BMP-2 in craniofacial reconstruction. BMP-2 is a viable option for craniofacial reconstruction to decrease donor-site morbidity or when alternatives are contraindicated. It is not recommended for routine use or in the oncologic setting but should currently be reserved as an alternative therapy for complex cases with limited options.

Bone morphogenetic proteins are a promising, emerging option for complex craniofacial reconstruction. Future directions of BMP-2 therapies will become apparent as data from prospective randomized trials emerges.
Clinical Features of Chinese Sporadic Leber Hereditary Optic Neuropathy Caused by Rare Primary mtDNA Mutations
Authors: Cui Shilei , Yang Ling , Jiang Hanqiu , Peng Jingting , Shang Jun , Wang Jiawei , Zhang Xiaojun
Published: May 2019

Objective:

The primary aim of this study was to describe clinical features of Chinese sporadic Leber hereditary optic neuropathy (LHON) caused by rare primary mitochondrial DNA (mtDNA) mutations.

Methods:

We characterized a Chinese patient cohort with rare primary mtDNA mutations at Beijing Tongren Hospital between 2015 and 2018. The clinical features of these patients were retrospectively recorded and analyzed.

Results:

Sixteen patients with LHON who had the selected rare primary mutations, including m.4171C>A (3 patients), m.10197G>A (1 patient), m.14459G>A (4 patients), and m.14502T>C (8 patients), were evaluated. The mean age at disease onset was 15 ± 6 years, and the male to female ratio was 15:1. Of 32 eyes of all patients, 75% (24/32) had a worst Snellen best-corrected visual acuity ≤0.1 (worse than 20/200), while 67% (2/3) who were carrying the m.4171C>A mutation experienced significant visual improvement. In addition, 40% (2/5) of patients with LHON carrying only m.14502T>C mutation had only mild visual impairment. Isolated manifestations of LHON was present in 94% (15/16) of all patients; 1 patient with the m.14459G>A mutation had LHON plus dystonia. Brain MRI T2 short tau inversion recovery sequences demonstrated optic atrophy in 62.5% (10/16); increased T2 signal in the optic nerve was found in 38% (6/16) of patients. The patient with LHON plus dystonia demonstrated optic atrophy and increased T2 signal in basal ganglia.

Conclusion:

Patients with LHON and rare primary mutations have diverse clinical phenotypes. Those with the m.4171C>A mutation are more likely to have a good visual prognosis, while the m.14502T>C mutation may play a synergistic role in disease onset. Increased signal in the optic nerve on MRI is not rare, and this feature should not exclude LHON as the potential cause for optic neuropathy.
Virus-like particles in a new vaccination approach against infectious laryngotracheitis
Authors: Schädler Julia , Sigrist Brigitte , Meier Simone M. , Albini Sarah , Wolfrum Nina
Published: May 2019

Gallid alphaherpesvirus 1 (syn. infectious laryngotracheitis virus; ILTV) is the causative agent of infectious laryngotracheitis, a respiratory disease of chickens causing substantial economic losses in the poultry industry every year. Currently, the most efficient way to achieve protection against infection is immunization with live-attenuated vaccines. However, this vaccination strategy entails the risk of generating new pathogenic viruses resulting from spontaneous mutations or from recombination with field strains. This work presents a new approach based on virus-like particles (VLPs) displaying ILTV glycoproteins B (gB) or G (gG) on their surface. The main focus of this pilot study was to determine the tolerability of VLPs delivered in ovo and intramuscularly (i.m.) into chickens and to investigate the nature of the immune response elicited. The study revealed that the new vaccines were well tolerated in hybrid layer chicks independent of the administration method (in ovo or i.m.). Upon in ovo injection, vaccination with VLP-gG led to an antibody response, while a cellular immune response in VLP-gB-immunized chickens was hardly detectable. Since the administration of VLPs had no visible side effects in vivo and was shown to elicit an antibody-based immune response, we anticipate that VLPs will become a valuable platform for the development of new safe vaccines for poultry.
Heterogeneous multi-scale framework for cancer systems models and clinical applications
Authors: Ghosh Alokendra , Radhakrishnan Ravi
Published: May 2019

Clinical Cancer models need to incorporate a wide variety of patient data and tumor heterogeneity which requires integration of multiple models. Due to differences in time and length scales of individual processes, such a model integration is a challenging task. Here we have developed an integrated framework combining ErbB receptor mediated Ras-MAPK and PI3K/AKT pathway with p53 mediated DNA damage response pathway. We have applied this in a clinical setting to predict patient specific response of different treatments in cancers of prostate, lung and kidney.
A gene filter for comparative analysis of single-cell RNA-sequencing trajectory datasets
Authors: Wang Yutong , Thong Tasha , Saligrama Venkatesh , Colacino Justin , Balzano Laura , Scott Clayton
Published: May 2019

Unsupervised feature selection, or gene filtering, is a common preprocessing step to reduce the dimensionality of single-cell RNA sequencing (scRNAseq) data sets. Existing gene filters operate on scRNAseq datasets in isolation from other datasets. When jointly analyzing multiple datasets, however, there is a need for gene filters that are tailored to comparative analysis. In this work, we present a method for ranking the relevance of genes for comparing trajectory datasets. Our method is unsupervised, i.e., the cell metadata are not assumed to be known. Using the top-ranking genes significantly improves performance compared to methods not tailored to comparative analysis. We demonstrate the effectiveness of our algorithm on previously published datasets from studies on preimplantation embryo development, neurogenesis and cardiogenesis.
Transcriptional Signatures of the Hierarchical Chronnectome Organization in the Human Brain
Authors: Liu Jin , Xia Mingrui , Wang Xindi , Liao Xuhong , He Yong
Published: May 2019

The chronnectome of the human brain represents the dynamics of functional organization in interacting regions, but its organizational principle and the underlying molecular mechanisms remain unclear. Using task-free fMRI and postmortem gene expression data, we conduct a transcriptome-chronnectome association study to investigate the spatial configurations of dynamic brain networks and their associations with transcriptional signatures. We reveal a spatial layout of network dynamics in the human brain chronnectome that reflects the cortical hierarchy and myelin content spanning from primary to transmodal areas. We further identify the transcriptional signature of this layout, with the top-related genes enriched for the ion channel and mitochondria terms. Moreover, the expression of these genes significantly predicts brain dynamics-behavior coupling. These findings highlight the hierarchical organizing principle and underlying molecular basis of the spatial configurations of dynamic brain networks, thereby contributing to our understanding of the associations among gene expression, network dynamics, and behaviors.
Hip retraction enhances walking stability on a ramp: an equilibrium point hypothesis-based study
Authors: Bahramian Alireza , Shamsi Elham , Towhidkhah Farzad , Jafari Sajad
Published: May 2019

Hip retraction is a phenomenon observed in human walking. The swing leg rotates backward at the end of the motion. Its positive effect on motion stability was reported in the literature based on some simple models for running or walking. In this study, it is shown that hip retraction angle increases in humans during their ascending and descending walk on a stair. In previous studies, hip retraction was modeled by defining a proper motion for the swing leg. According to the equilibrium point hypothesis, the central nervous system (CNS) defines only the equilibrium point(s) and stiffness(es) for body joint(s) to control the human motion. Human body motion emerges as its natural response as a result of the external forces and the defined equilibrium points of joints. Considering the hip torque as a spring-like model with an equilibrium point and stiffness, this study revealed that the hip retraction can be generated by the natural response of the swing leg. Besides, the stabilizing effect of hip retraction was demonstrated by a model for human’s ascending and descending walking on a ramp with a range of positive and negative angles, respectively. The findings suggest that the CNS needs to define equilibrium point just ahead of the stance leg to take advantage of the hip retraction effect on ascending and descending walks on a ramp.
Bayesian inference of differentially expressed transcripts and their abundance from multi-condition RNA-seq data
Authors: Chen Xi
Published: May 2019

Deep sequencing of bulk RNA enables the differential expression analysis at transcript level. We develop a Bayesian approach to directly identify differentially expressed transcripts from RNA-seq data, which features a novel joint model of the sample variability and the differential state of individual transcripts. For each transcript, to minimize the inaccuracy of differential state caused by transcription abundance estimation, we estimate its expression abundance together with the differential state iteratively and enable the differential analysis of weakly expressed transcripts. Simulation analysis demonstrates that the proposed approach has a superior performance over conventional methods (estimating transcription expression first and then identifying differential state), particularly for lowly expressed transcripts. We further apply the proposed approach to a breast cancer RNA-seq data of patients treated by tamoxifen and identified a set of differentially expressed transcripts, providing insights into key signaling pathways associated with breast cancer recurrence.
DNSS2: improvedab initioprotein secondary structure prediction using advanced deep learning architectures
Authors: Hou Jie , Guo Zhiye , Cheng Jianlin
Published: May 2019

Motivation

Accurate prediction of protein secondary structure (alpha-helix, beta-strand and coil) is a crucial step for protein inter-residue contact prediction andab initiotertiary structure prediction. In a previous study, we developed a deep belief network-based protein secondary structure method (DNSS1) and successfully advanced the prediction accuracy beyond 80%. In this work, we developed multiple advanced deep learning architectures (DNSS2) to further improve secondary structure prediction.

Results

The major improvements over the DNSS1 method include (i) designing and integrating six advanced one-dimensional deep convolutional/recurrent/residual/memory/fractal/inception networks to predict secondary structure, and (ii) using more sensitive profile features inferred from Hidden Markov model (HMM) and multiple sequence alignment (MSA). Most of the deep learning architectures are novel for protein secondary structure prediction. DNSS2 was systematically benchmarked on two independent test datasets with eight state-of-art tools and consistently ranked as one of the best methods. Particularly, DNSS2 was tested on the 82 protein targets of 2018 CASP13 experiment and achieved the best Q3 score of 83.74% and SOV score of 72.46%. DNSS2 is freely available at:https://github.com/multicom-toolbox/DNSS2.
A Novel L-Serine Exporter and Its Positive Regulator in Corynebacterium glutamicum
Authors: Zhang Xiaomei , Gao Yujie , Chen Ziwei , Xu Guoqiang , Zhang Xiaojuan , Li Hui , Shi Jinsong , Koffas Mattheos , Xu Zhenghong
Published: May 2019

Exporters play an essential role in the fermentative production of amino acids. In Corynebacterium glutamicum, ThrE, which can export L-threonine and L-serine, is the only identified L-serine exporter so far. In this study, a novel L-serine exporter NCgl0580 was identified and characterized in C. glutamicum ΔSSAAI (SSAAI), and named as SerE (encoded by serE). Deletion of serE in SSAAI led to a 56.5% decrease in L-serine titer, whereas overexpression of serE compensated for the lack of serE with respect to L-serine titer. A fusion protein with SerE and enhanced green fluorescent protein (EGFP) was constructed to confirm that SerE localized at the plasma membrane. The function of SerE was studied by peptide feeding approaches, and the results showed that SerE is a novel exporter for L-serine and L-threonine in C. glutamicum. Subsequently, the interaction of a known L-serine exporter ThrE and SerE was studied, and the results suggested that SerE is more important than ThrE in L-serine export in SSAAI. Probe plasmid and electrophoretic mobility shift assays (EMSA) revealed NCgl0581 as the transcriptional regulator of SerE. Comparative transcriptomics between SSAAI and the NCgl0581 deletion strain showed that NCgl0581 regulated the transcription of 115 genes in C. glutamicum, among which the transcriptional level of NCgl0580 decreased 280-fold in a NCgl0581 deletion strain, indicating that NCgl0581 is a positive regulator of SerE. Thus, this study provides a novel target for L-serine and L-threonine export engineering as well as a novel global transcriptional regulator NCgl0581 in C. glutamicum.

Importance

Exporters are gaining increasing attention for improving industrial production of amino acids. This study identified a novel exporter NCgl0580 for L-serine and L-threonine in C. glutamicum, and its positive regulator (NCgl0581), which was shown to be a novel global transcriptional regulator in C. glutamicum. This study provides a new target for engineering efflux of L-serine and L-threonine, expands the exporter and transcriptional regulator family, and enriches our understanding of amino acid transport system in C. glutamicum.
Dynamic Changes of G-CSF etc. Nine Cytokines in Mouse Bloodstream Infection Models of Staphylococcus aureus and Klebsiella pneumoniae and their Clinical Performances
Authors: He Shang , Yang Ming , Li Xinjun , Chen Chen , Yating Ma , Wang Chi , Yang Jiyong , Wang Chengbin
Published: May 2019

Blood culture has been considered as the gold standard to diagnose the bacterial bloodstream infection, but its long turnaround time gravely obstructed the clinical medication by physicians. Cytokines play an important role in bacterial infection. The purpose of this study was to monitor the kinetic changes of nine cytokines in mouse infection models and to infer their diagnostic value in early infection.

Methods

The mouse bloodstream infection model of Staphylococcus aureus and the other model of Staphylococcus aureus and Klebsiella pneumoniae were constructed respectively, and the dynamic changes of nine cytokines were monitored within 48 hours after infected with 1/2 LD50 bacterial concentration. Cytokines with significant differences between the two groups and PBS control group from 0 to 6 hours after infection were selected for theoretical proof in patient sera that were clearly diagnosed as bloodstream infection. Receiver operating characteristic (ROC) curve analysis was conducted to determine the clinical differentiation of different cytokines.

Results

Two models of S.aureus and K. pneumoniae bloodstream infection in mice were constructed successfully. In the two mouse models, six of the nine cytokines monitored were different (P<0.05) in each experimental group. In the 121 patient sera samples, three cytokines, IL-6, IL-12p70 and G-CSF in the infection groups and control group had showed differences. In particular, AUC of G-CSF was 0.9051, the accuracy is better than IL-6 for diagnosing the infection. In addition, only G-CSF was significantly different between the two infection groups and in the analysis of ROC curve, AUC is equal to 0.735.

Conclusions

G-CSF can not only judge the bacterial infection and non-infection, but also distinguish the infection of S.aureus from K. pneumoniae.
DNA writing at a single genomic site enables lineage tracing and analog recording in mammalian cells
Authors: Loveless Theresa B. , Grotts Joseph H. , Schechter Mason W. , Forouzmand Elmira , Carlson Courtney K. , Agahi Bijan S. , Liang Guohao , Ficht Michelle , Liu Beide , Xie Xiaohui , Liu Chang C.
Published: May 2019

The study of intricate cellular and developmental processes in the context of complex multicellular organisms is difficult because it can require the non-destructive observation of thousands, millions, or even billions of cells deep within an animal. To address this difficulty, several groups have recently reported CRISPR-based DNA recorders that convert transient cellular experiences and processes into changes in the genome, which can then be read by sequencing in high-throughput. However, existing DNA recorders act primarily byerasingDNA: they use the random accumulation of CRISPR-induced deletions to record information. This is problematic because in the limit of progressive deletion, no record remains. Here, we present a new type of DNA recorder that acts primarily bywritingnew DNA. Our system, called CHYRON (Cell HistorY Recording by Ordered iNsertion), inserts random nucleotides at a single locus in temporal orderin vivoand can be applied as an evolving lineage tracer as well as a recorder of user-selected cellular stimuli. As a lineage tracer, CHYRON allowed us to perfectly reconstruct the population lineage relationships among 16 groups of human cells descended from four starting groups that were subject to a series of splitting steps. In this experiment, CHYRON progressively wrote and retained base insertions in 20% percent of cells where the average amount written was 8.4 bp (~14.5 bits), reflecting high information content and density. As a stimulus recorder, we showed that when the CHYRON machinery was placed under the control of a stress-responsive promoter, the frequency and length of writing reflected the dose and duration of the stress. We believe CHYRON represents a conceptual advance in DNA recording technologies where writing rather than erasing becomes the primary mode of information accumulation. With further engineering of CHYRON’s components to increase writing efficiency, CHYRON should lead to single-cell-resolution recording of lineage and other information through long periods of time in complex animals or tumors, advancing the pursuit of a full picture of mammalian development.
The fitness cost of mismatch repair mutators inSaccharomyces cerevisiae: partitioning the mutational load
Authors: Galeota-Sprung Benjamin , Guindon Breanna , Sniegowski Paul
Published: May 2019

Mutational load is the depression in a population’s mean fitness that results from the continual influx of deleterious mutations. Here, we directly estimate the mutational load in a population of haploidSaccharomyces cerevisiaethat are deficient for mismatch repair. We partition the load in haploids into two components. To estimate the load due to nonlethal mutations, we measure the competitive fitness of hundreds of randomly selected clones from both mismatch repair-deficient and - proficient populations. Computation of the mean clone fitness for the mismatch repair-deficient strain permits an estimation of the nonlethal load, and the histogram of fitness provides an interesting visualization of a loaded population. In a separate experiment, in order to estimate the load due to lethal mutations (i.e. the lethal mutation rate), we manipulate thousands of individual pairs of mother and daughter cells and track their fates. These two approaches yield point estimates for the two contributors to load, and the addition of these estimates is nearly equal to the separately measured short-term competitive fitness deficit for the mismatch repair-deficient strain. This correspondence suggests that there is no need to invoke direct fitness effects to explain the fitness difference between mismatch repair-deficient and - proficient strains. Assays in diploids are consistent with deleterious mutations in diploids tending towards recessivity. These results enhance our understanding of mutational load, a central population genetics concept, and we discuss their implications for the evolution of mutation rates.