bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of human leukocyte antigen alleles and supertypes with immunogenicity of oral rotavirus vaccine given to infants in China
Authors: Liu Yueyue , Guo Tai , Yu Qingchuan , Zhang Haowen , Du Jialiang , Zhang Yunqi , Xia Shengli , Yang Huan , Li Qihan
Published: October 2018

Rotavirus (RV) vaccines show distinct immunogenicity in dozens of clinical trials, which is associated with multiple host and environmental factors. Previous research has demonstrated that the highly polymorphic human leukocyte antigen (HLA) system plays an essential role in regulating immune response to a variety of vaccines. This study aims to investigate the relationship between HLA polymorphisms and immunogenicity of RV vaccine.

A nested case-control study was carried out among infants enrolled in phase III clinical trial of trivalent human-lamb reassortant vaccine (RV3) in Henan province, China. Serum RV specific immunoglobulin A (RV-IgA) was detected before and after a 3-dose vaccination series, followed by calculation of seroconversion rates. Seroconversion was defined as a 4-fold or greater increase in RV-IgA titers between pre-vaccination and 1-month post-dose 3 vaccination. The infants who seroconverted were defined as responders, and the others without seroconversion were considered as non-responders. Their HLA genotypes were obtained by using the sequence-based typing method. The HLA allele and supertype frequencies of 2 groups were analyzed statistically.

Eighty-three of 133 infants seroconverted after vaccination. Twenty-one HLA-A, 45 HLA-B, 24 HLA-Cw, 29 HLA-DRB1 and 16 HLA-DQB1 distinct alleles were detected. The frequency of HLA-B∗4001 (corrected P = .01, adjusted OR = 0.152, 95% CI = 0.048–0.475) in non-responder group was significantly higher than that in responder group. Furthermore, significant association was found between HLA-B44 supertype (corrected P = .02, adjusted OR = 0.414, 95% CI = 0.225–0.763) and RV non-response.

Certain HLA allele (HLA-B∗4001) and supertype (HLA-B44) are potentially associated with non-response after immunization with the novel RV3 vaccine in Chinese infants.
Evidence supporting FDA approval and CMS national coverage determinations for novel medical products, 2005 through 2016
Authors: Roginiel Aliya C. , Dhruva Sanket S. , Ross Joseph S.
Published: October 2018

Food and Drug Administration (FDA) and Centers for Medicare and Medicaid Services (CMS) rely on evidence from clinical trials when approving a therapeutic for marketing and insurance coverage in the US, respectively. No study has compared the quality and quantity of evidence examined by these agencies.

To characterize evidence used by FDA and CMS to support marketing approval and National Coverage Determinations (NCDs), respectively, of novel therapeutics reviewed for CMS coverage from 2005 through 2016.

A cross-sectional study of clinical trials described in FDA approval documents and CMS NCD memoranda. We compared the number of clinical trials used by each agency as well as the following characteristics among original clinical trials: study size, randomization, double-blinding, and control arm.

Twelve medical products met our inclusion criteria. FDA approvals of these products were based on 22 pivotal trials. CMS NCDs were based on 27 original clinical trials; 14 clinical trials were used by both agencies. Between FDA pivotal and CMS original clinical trials, there was no significant difference in study size (P = .53), use of randomization (P = .75), double-blinding (P = .55), or control arm (P = .54). There was no statistically significant difference in median age between participants in trials reviewed by CMS versus those reviewed by FDA (62 vs 59 years, P = .26). The median time from FDA approval to publication of CMS NCD memorandum was 17 (interquartile range, 13–36) months.

FDA approvals and CMS NCDs are based on a similar number and quality of trials, although trial participants are not reflective of the Medicare population, and the process of finalizing coverage determinations requires an additional 17 months.
Vitamin D supplementation to prevent vitamin D deficiency for children with epilepsy
Authors: Khalifah Reem Al , Hudairi Abrar , Homyani Doua Al , Hamad Muddathir H. , Bashiri Fahad A.
Published: October 2018

Background

: Vitamin D deficiency is highly prevalent among children with epilepsy. Lack of high-quality evidence led to variability among scientific societies recommendations. Therefore, we aim to determine the efficacy of different common doses used in the pediatric practice to maintain optimal 25-hydroxy vitamin D (25 [OH] vitamin D) level in children with epilepsy and normal baseline 25 (OH) vitamin D level over 6 months of supplementation.

Methods

: This is a protocol for phase IV pragmatic randomized superiority controlled open-label trial at King Saud University Medical City in Riyadh. Children with epilepsy and receiving chronic antiepliptic medication and normal baseline 25 (OH) vitamin D level will be randomly assigned to receive Cholecalciferol 400 IU/day versus 1000 IU/day for 6 months. Our primary outcome is the proportion of children with vitamin D insufficiency (25 (OH) vitamin D level < 75nmol/L) at 6 months. Secondary outcomes include seizure treatment failure, seizure frequency, parathyroid hormone (PTH) levels, bone mineral density, and safety.

Discussion: Our trial is set out to evaluate the efficacy of common different vitamin D maintenance doses on 25 (OH) vitamin D level, seizure control, and bone health for children with epilepsy. The results of our study will possibly help in shaping current vitamin D guidelines for vitamin D supplementation in children with epilepsy and provide a link between 25 (OH) vitamin D level and seizure control.
An Uncommon Presentation of a Primary Bone Tumor: Anti-AMPA (Anti–α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic acid) Receptor Limbic/Paraneoplastic Encephalitis as a Presenting Feature of Ewing Sarcoma
Authors: Koh Daniel , Lau Theodore , Teoh Evonne , Lau Kenneth K.
Published: October 2018

Anti-AMPA (anti–α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor limbic encephalitis is a rare autoimmune syndrome. It can be associated with an underlying malignancy, such as lung, breast, or thymus. We are reporting a case of a 19-year-old patient who presented with a 2-week history of confusion and short-term memory loss. A magnetic resonance imaging of brain showed increased T2 hyperintensity within the hippocampi bilaterally. Cerebrospinal fluid analysis was positive for anti-AMPA receptor antibodies. A computed tomography revealed multiple pulmonary metastases as well as an expansile lucent and sclerotic lesion in the ilium, which was subsequently biopsied. Histopathology confirmed a diagnosis of Ewing sarcoma (ES). Fluorescence in situ hybridization testing of the specimen identified EWSR1 (22q12.2) signal rearrangements in 80% of cells scored. To date, this is the first case report describing anti-AMPA receptor limbic/paraneoplastic encephalitis as a presenting feature of ES. Although it is rare, the possibility of ES may be considered in young patients presenting with anti-AMPA receptor limbic encephalitis.
Effects of functional electrical stimulation-cycling on shoulder pain and subluxation in patients with acute–subacute stroke: a pilot study
Authors: Karaahmet Ozgur Z. , Gurcay Eda , Unal Zeynep K. , Cankurtaran Damla , Cakci Aytul
Published: October 2018

Functional electrical stimulation (FES)-cycling is a technique used to provide voluntary muscle contraction during a functional task. The aims were primarily to determine the effects of FES-cycling on shoulder pain and subluxation, and secondarily to evaluate the improvement of upper extremity motor function in patients with acute–subacute stroke patient. In this prospective trial, 21 patients with acute–subacute stroke, randomly assigned into the FES-cycling group or the standard rehabilitation program (control group). Analyses of shoulder subluxation were carried out by radiography. The numeric rating scale was used to evaluate the intensity of pain, Fugl-Meyer and Frenchay arm tests for motor function, and functional independence measure for functional status. The outcome data were evaluated at baseline and at the end of 4-week treatment. Intragroup comparisons showed improvement of acromiohumeral distance, Fugl-Meyer assessment, and functional independence measure in both groups after treatment. In intergroup comparison, FES-cycling group exerted better outcomes in shoulder pain compared with the control group (P=0.015). Correlation analyses demonstrated only positive correlation between shoulder subluxation and pain (P=0.022). FES-cycling was superior to standard rehabilitation therapy for shoulder pain relief in patients with acute–subacute stroke. Therefore, combining FES-cycling with a standard rehabilitation program alleviates shoulder pain and may prevent development of shoulder subluxation over time.
Organizational Factors Associated With Technical Efficiency of Nursing Care in US Intensive Care Units
Authors: Min Ari , Scott Linda D. , Park Chang , Vincent Catherine , Ryan Catherine J.
Published: October 2018

Background:

Few studies have evaluated technical efficiency of nursing care, and no such studies have been conducted in intensive care units (ICUs).

Purpose:

To explore relative technical efficiency of US ICUs and identify organizational factors associated with efficiency in providing quality of nursing care.

Methods:

A total of 404 adult ICUs from the 2014 National Database of Nursing Quality Indicators were included. Data envelopment analysis was used to estimate technical efficiency, and multilevel modeling was employed to determine effects of organizational factors on efficiency.

Results:

Nurse-to-patient ratio showed the strongest positive correlation with technical efficiency. Units in non-Magnet and small-size hospitals had higher technical efficiency than those in Magnet and medium- or large-size hospitals.

Conclusions:

A higher nurse-to-patient ratio greatly improved technical efficiency of nursing care in ICUs and the effect differed between hospitals. Administrators and policy makers can translate the study findings into management strategies to provide efficient nursing care in ICUs.
A Comparison of the Nulliparous-Term-Singleton-Vertex and Society of Maternal-Fetal Medicine Cesarean Birth Metrics Based on Hospital Size
Authors: Shields Laurence E. , Walker Suzan , Hedriana Herman L. , Wiesner Suzanne , Pelletreau Barbara , Hitti Jane , Benedetti Thomas J.
Published: October 2018

(Abstracted from Am J Perinatol 2018;35:390–396)

Cesarean delivery rate is a commonly used health care metric to evaluate quality of care. Some states have proposed using it to select hospitals to provide care to pregnant women paid for by state-funded health care exchanges.
Association of Prenatal Ultrasonography and Autism Spectrum Disorder
Authors: Rosman N. Paul , Vassar Rachel , Doros Gheorghe , DeRosa James , Froman Allison , DiMauro Audrey , Santiago Sherry , Abbott Jodi
Published: October 2018

(Abstracted from JAMA Pediatr 2018;172(4):336–344)

The prevalence of autism spectrum disorder (ASD) has increased over the past several decades. Despite ongoing identification of genetic causes, there exists mounting evidence that environmental exposures may account for a significant amount of this increase in incidence.
Germline De Novo Mutation Clusters Arise During Oocyte Aging in Genomic Regions With High Double-Strand-Break Incidence
Authors: Goldmann Jakob M. , Seplyarskiy Vladimir B. , Wong Wendy S. W. , Vilboux Thierry , Neerincx Pieter B. , Bodian Dale L. , Solomon Benjamin D. , Veltman Joris A. , Deeken John F. , Gilissen Christian , Niederhuber John E.
Published: October 2018

(Abstracted from Nat Genet 2018;50:487–492)

Germline de novo mutations (DNMs) arise spontaneously in parental gametes and are both drivers of evolution and a common cause of sporadic disorders. The total number of DNMs is highly correlated with paternal age and with maternal age to a lesser extent.
Development of Silicone Hydrogel Antimicrobial Contact Lenses with Mel4 Peptide Coating
Authors: Dutta Debarun , Kamphuis Bjorn , Ozcelik Berkay , Thissen Helmut , Pinarbasi Rasim , Kumar Naresh , Willcox Mark D. P.
Published: October 2018

SIGNIFICANCE

This study investigated the development of an antimicrobial coating on silicone hydrogel contact lenses that may have the capacity to reduce contact lens–related infection and inflammatory events.

PURPOSE

The purpose of this study was to develop an effective antimicrobial coating for silicone hydrogel contact lenses by attachment of Mel4 peptide.

METHODS

Lotrafilcon A, comfilcon A, somofilcon A, senofilcon A, and lotrafilcon B silicone hydrogel contact lenses were plasma coated with acrylic acid followed by Mel4 antimicrobial peptide immobilization by covalent coupling. Peptide immobilization was quantified by x-ray electron spectroscopy. Contact lens diameter, base curve, center thickness, and lens surface wettability were measured by captive-bubble contact-angle technique. Antimicrobial activity of the lenses was determined against Pseudomonas aeruginosa and Staphylococcus aureus by viable plate count and also after soaking with artificial tears solution for 1 day. In vivo safety and biocompatibility were determined in an animal model for 1 week.

RESULTS

Mel4 peptide–coated silicone hydrogel contact lenses were associated with high antimicrobial inhibition (>2 log), except for lotrafilcon B and senofilcon A. Lotrafilcon B did not exhibit any activity, whereas senofilcon A showed 1.4- and 0.7-log inhibition against P. aeruginosa and S. aureus, respectively. X-ray electron spectroscopy revealed significant increases in the lens surface–bound amide nitrogen in all contact lenses except for lotrafilcon B. All contact lens parameters remained unchanged except for the base curve and center thickness for senofilcon A. Mel4 immobilization was associated with a decrease in contact angle. Mel4-coated contact lens wear was not associated with any signs or symptoms of ocular irritation in a rabbit model study. Reduced antimicrobial activity was observed with all the lenses after soaking with artificial tears solution or rabbit wear.

CONCLUSIONS

Mel4 antimicrobial coating may be an effective option for development of antimicrobial silicone hydrogel contact lenses.
Management of Wheezy Preschoolers in the Emergency Department
Authors: Currie Gillian , Crotts Jennifer , Nettel-Aguirre Alberto , Johnson David , Stang Antonia
Published: October 2018

Objectives

This study aimed to elicit pediatric emergency physician's treatment choices for preschool-aged children with wheeze, determine the characteristics of the presenting child that influence treatment choices, and determine whether there is clinical equipoise by eliciting physician willingness to enroll these children in a placebo-controlled trial of corticosteroids.

Methods

Discrete choice experiments varying the characteristics of the presenting child were designed to elicit Canadian emergency physician's treatment choices, both in the emergency department (ED) and at discharge, for young children presenting with wheeze and their willingness to enroll in a randomized controlled trial (RCT).

Results

Most physicians chose to treat children with albuterol both in the ED and at discharge for all clinical scenarios. The proportion of physicians who chose to treat children with oral corticosteroids both in the ED and at discharge varied widely (from 12% to 81%) across all scenarios. Physician preference whether preschool children with wheeze should be treated with corticosteroids varied depending on the child's age, history of atopy, and previous and continuous wheeze. Between 73% and 86% of physicians were willing to enroll these children in an RCT indicating clinical equipoise.

Conclusions

Physician treatment choices varied widely indicating clinical equipoise as to the effectiveness of corticosteroids in this population of patients. Management choices with respect to albuterol and corticosteroids were not consistent with published national and international guidelines. In line with this finding, physician's considerable willingness to enroll these children in an RCT may suggest that they are seeking guidance on how to manage these patients.
Prehospital Analgesic Administration by Parents for Pain Relief in Children
Authors: Conrad Christina , Soni Parita , Coorg Vasanth , Thompson Benjamin , Muenzer Jared , Timmons Zebulon , Bulloch Blake
Published: October 2018

Purpose

Undertreatment of pain by caregivers before presentation to the pediatric emergency department (ED) has been well documented. What has yet to be elucidated are the reasons why caregivers fail to adequately treat pain before arrival in the ED and whether there are differences based on ethnic background or age of the child. The objectives of this study were to determine the barriers to giving pain medication for injuries before ED arrival and to determine if there are any ethnic- or age-related variations to giving pain relief at home.

Methods

This prospective descriptive study was conducted in the ED at a tertiary care, freestanding children's hospital with a current annual census of approximately 80,000. An anonymous prospective questionnaire was given to caregivers of children between 2 and 17 years of age presenting to the ED between August 2013 and September, 2014. The study population was obtained as a convenience sample. All were self-referred with chief complaints of head, ear, or extremity pain. The questionnaire asked about pain medications and doses given at home as well as the reasons parents gave medication or refused to give pain medication before arrival. Charts were then abstracted to obtain demographic information and care received in the ED.

Results

A total of 154 (45.6%) of the 338 patients enrolled did not receive pain relief before coming to the ED. There were no differences in pain medication received at home based on ethnicity (P = 0.423) or age (P = 0.580). Parents could choose from a list of multiple reasons as to why pain medications were given and/or free text their own answer. The main reasons given by parents were that the accident did not happen at home (28.6%) and that they did not have time to give pain relief before coming to the ED (13%). Other common answers were “had no pain relievers at home” (12.4%) or “afraid it would be wrong/harmful/did not want to mask symptoms” (9.2%). Seventeen parents responded that their child did not complain of pain. Overall, only 28.1% of participants stated lack of pain medications at home.

Conclusions

In this study, approximately half of all children receive an analgesic for their painful condition before coming to the ED. Continued education regarding pain relief before coming to the ED is needed. Future studies will focus on educating parents to provide analgesia at home.
Unique aspects of clinical trials of invasive therapies for chronic pain
Authors: Cohen Steven P. , Wallace Mark , Rauck Richard L. , Stacey Brett R.
Published: October 2018

Nearly all who review the literature conclude that the role of invasive procedures to treat chronic pain is poorly characterized because of the lack of “definitive” studies. The overt nature of invasive treatments, along with the risks, technical skills, and costs involved create challenges to study them. However, these challenges do not completely preclude evaluating invasive procedure effectiveness and safety using well-designed methods. This article reviews the challenges of studying outcomes of invasive therapies to treat pain and discuss possible solutions. Although the following discussion can apply to most invasive therapies to treat chronic pain, it is beyond the scope of the article to individually cover every invasive therapy used. Therefore, most of the examples focus on injection therapies to treat spine pain, spinal cord stimulation, and intrathecal drug therapies.
Comparison of Abdominal Computed Tomographic Enhancement and Organ Lesion Depiction Between Weight-Based Scanner Software Contrast Dosing and a Fixed-Dose Protocol in a Tertiary Care Oncologic Center
Authors: Jensen Corey T. , Blair Katherine J. , Wagner-Bartak Nicolaus A. , Vu Lan N. , Carter Brett W. , Sun Jia , Bathala Tharakeswara K. , Gupta Shiva
Published: October 2018

Objective

This study aimed to evaluate the quality of enhancement and solid-organ lesion depiction using weight-based intravenous (IV) contrast dosing calculated by injector software versus fixed IV contrast dose in oncologic abdominal computed tomographic (CT) examinations.

Methods

This institutional review board–exempt retrospective cohort study included 134 patients who underwent single-phase abdominal CT before and after implementation of weight-based IV contrast injector software. Patient weight, height, body mass index, and body surface area were determined. Two radiologists qualitatively assessed examinations (4 indicating markedly superior to −4 indicating markedly inferior), and Hounsfield unit measurements were performed.

Results

Enhancement (estimated mean, −0.05; 95% confidence interval [CI], −0.19 to 0.09; P = 0.46) and lesion depiction (estimated mean, −0.01; 95% CI, −0.10 to 0.07; P = 0.79) scores did not differ between CT examinations using weight-based IV contrast versus fixed IV contrast dosing when a minimum of 38.5 g of iodine was used. However, the scores using weight-based IV contrast dosing were lower when the injector software calculated and delivered less than 38.5 g of iodine (estimated mean, −0.81; 95% CI, −1.06 to −0.56; P < 0.0001). There were no significant differences in measured Hounsfield units between the CT examinations using weight-based IV contrast dosing versus fixed IV contrast dosing.

Conclusions

Oncologic CT image quality was maintained or improved with weight-based IV contrast dosing using injector software when using a minimum amount of 38.5 g of iodine.
CT Window Blending for Evaluation of Multicompartmental Thoracic Pathology
Authors: Hammer Mark M. , Mandell Jacob C.
Published: October 2018

Standard computed tomography windows are limited in the thorax because they can only display 1 tissue at a time. Computed tomography window blending allows for simultaneous viewing of all 3 tissues in a single image, which may improve evaluation of diseases that contiguously affect multiple compartments. In this article, we use examples to illustrate the utility of window blending in aggressive infections, metastatic cancer, and penetrating trauma.
Free Latissimus Dorsi Myocutaneous Flap in a 6-Month-Old Child for Reconstruction of a Temporal Fossa Defect After Teratoma Resection
Authors: Fried Frederik W. , Beier Justus P. , Bohr Christopher , Iro Heinrich , Horch Raymund E. , Arkudas Andreas
Published: October 2018

Although free flap reconstruction has already gained widespread acceptance in pediatric patients, little is known about the outcome of free tissue transfer in head and neck reconstruction in pediatric patients. We present a case of a 6-month-old boy with a large volume deficit in the right temporal fossa after resection of a teratoma. This led to a large volume deficit with widely undermined skin margins. Therefore, we provided volume augmentation by microsurgical free latissimus dorsi myocutaneous flap transplantation. Intraoperative use of laser-assisted indocyanine green angiography indicated excellent flap perfusion. Postoperative magnetic resonance imaging showed adequate flap perfusion with no signs of flap necrosis. To our best knowledge, this case presents the youngest patient who underwent free flap transplantation in the head and neck region. Our case demonstrates that microvascular surgery can play an important role in particular cases in pediatric oncology, even in very young patients.
Microsurgical Treatment of Ruptured True Posterior Communicating Artery Aneurysm in the Distal Portion of the Posterior Communicating Artery
Authors: Yang Yonglin , Meng Xiangfu , Song Jiangquan , Nie Xiutao , Zhao Chao , Su Wandong
Published: October 2018

The true posterior communicating artery (PCoA) aneurysms in the distal portion of the posterior communicating artery are rare. The authors describe a 63-year-old woman with 1 true PCoA aneurysms in the distal portion of the PCoA, which was treated surgically through modified pterional approach. No neurologic deficit was present at the postoperative period. Although endovascular intervention is more and more widely used in the treatment of aneurysms, the authors have also emphasized that true PCoA aneurysms in the distal portion of the PCoA can also be surgically treated in suitable patients.
Achondroplasia: Orocraniofacial Features and Orthodontic-Surgical Management Guidelines Proposal
Authors: Pineau Mallouel , Farrow Emilie , Nicot Romain , Ferri Joël
Published: October 2018

In this study, the authors aimed to describe orocraniofacial features and to suggest orthodontic-surgical managements in achondroplasia, based on a literature review. The authors focused on skeletal and dentoalveolar malocclusion in order to highlight the place of orthognathic surgery, based on our experience of 3 patients. Maxillary hypoplasia in achondroplasia typically results in an Angle class III malocclusion with an anterior open bite. The other orocraniofacial features include enlarged calvarium, prominent forehead and frontal bossing, midface hypoplasia, elongated lower face and saddle-shaped nose due to lack of development of the nasomaxillary complex.

All our patients had a typical facial appearance but each of them had their own particularities regarding medical history and severity of the dentoskeletal dysmorphosis. Two of them were successfully treated by orthognathic surgery; the other declined surgical treatment and underwent orthopedic treatment only (anchorage plates). The treatment failure of this 3rd patient raises the question of the efficiency of anchorage plates in achondroplasia. In the light of the literature and our results, the authors conclude the need for personalized management based on age, medical history, severity of the dentoskeletal dysmorphosis, functional and/or esthetic disorders, and the patient's needs and requests. In any patient, orthodontic management should be initiated at an early age, and orthognathic surgery modalities should be personalized and adapted to each situation.
Leukocyte Transcriptional Response in Sepsis
Authors: Skibsted Simon , Bhasin Manoj K. , Henning Daniel J. , Jaminet Shou Ching , Lewandowski Jeffrey , Kirkegaard Hans , Aird William C. , Shapiro Nathan I.
Published: October 2018

Background:

The complex host response to sepsis is incompletely understood. The aim of this investigation is to use leukocyte RNA sequencing to characterize biological functions, cellular pathways, and key regulatory molecules driving sepsis pathophysiology.

Methods:

This was a prospective, observational study of emergency department patients with sepsis, at an urban, academic, tertiary care center. In the derivation cohort, we collected blood at enrollment and 90 days after hospital discharge allowing each patient to serve as an internal control. We performed RNA sequencing to quantify transcriptional expression changes during sepsis and non-sepsis states. We then performed unsupervised and supervised analyses, as well as functional and pathway analyses. We selected the top down and upregulated genes and key regulatory molecules for validation. Validation occurred in a cohort of septic and non-septic using real-time PCR.

Results:

The derivation cohort included 5 patients, and RNA sequencing revealed 916 unique mRNA transcripts differentially expressed during sepsis. Among these, 673 (73%) genes were upregulated, and 243 (27%) were downregulated. Functional enrichment analysis revealed a highly dynamic downstream effect of the transcriptional activity during sepsis. Of the 43 functional cellular pathways activated during sepsis, the top pathways were closely associated with inflammation and response to infection. Validation occurred in 18 septic and 25 non-septic control patients, with 34/45 (76%) of identified genes validated. The regulatory analysis identified several key regulators of sepsis.

Conclusions:

Highly dynamic transcriptional activity occurs in leukocytes during sepsis, activating key cellular pathways and master regulatory molecules that drive the sepsis process.
Accuracy Comparison Between Age-Adapted SOFA and SIRS in Predicting in-Hospital Mortality of Infected Children at China's PICU
Authors: Wu Zhiyuan , Liang Yafeng , Li Zhihao , Liu Guangjian , Zheng Jianbin , Zuo Yunlong , Li Lijuan , Cao Xiaojun , Zhang Jianhui , Liang Huiying
Published: October 2018

Objectives:

Sepsis-3 consensus suggests “the need to develop similar updated definitions for pediatric populations.” Sequential organ failure assessment (SOFA) and systemic inflammatory response syndrome (SIRS) criteria are two systems widely used to define the status of infection. However, it is still unclear whether SOFA is more accurate than SIRS in predicting children mortality in low- and middle-income countries. Thus, we validated the accuracy of age-adapted SOFA and SIRS in predicating the poor prognosis of infected children in China's pediatric intensive care unit (PICU).

Methods:

We performed a retrospective and observational cohort study of children admitted for infection to PICU in the hospital between January 1, 2009 and December 31, 2017. The indexes within 24 h after intensive care unit (ICU) admission were analyzed according to age-adapted SOFA and SIRS, and all data were sourced from the hospital's electronic health record database. The prognosis was illustrated with primary outcome and secondary outcome. Primary outcome referred to in-hospital mortality, and secondary outcome to in-hospital mortality or ICU length of stay ≥ 7 days. The predictive power of age-adapted SOFA and SIRS was compared using crude and adjusted area under the receiver operating characteristic curve (AUROC).

Results:

Of 1,831 PICU-admitted children due to infection, 164 (9.0%) experienced primary outcome, and 948 (51.8%) secondary outcome. Of 164 deaths, 65.9% were males (median age of 7.53 months, range of 2.67–41.00 months). Children who scored ≥ 2 in age-adapted SOFA or met two SIRS criteria accounted for 92.5% and 73.3%, respectively. In addition, age-adapted SOFA score of ≥2 predicted adverse outcome more accurately than pediatric SIRS (adjusted AUROC, 0.753; 0.713–0.796 vs. 0.674; 0.631–0.702; P < 0.001).

Conclusion:

Compared with SIRS criteria, age-adapted SOFA score of ≥ 2 enjoys a more accuracy in predicting in-hospital mortality of PICU-admitted children, and a higher sensitivity in identifying children with severe infection.
In Situ Simulation to Mitigate Threats to Participation in a Multicenter Clinical Trial in High-Acuity, Low-Frequency Setting
Authors: Chan Steven , Babcock Lynn , Geis Gary , Frey Mary , Robinson Venita , Kerrey Benjamin
Published: October 2018

Introduction

Multicenter clinical trials of high-acuity, low-frequency emergencies are expensive and resource intensive. Current standards for trial preparation have significant limitations. Our objective is to describe our use of in situ simulation (ISS) to identify and mitigate threats to enrollment, protocol adherence, and patient safety in preparation for a multicenter clinical trial of antiepileptics for status epilepticus in the emergency department.

Methods

This is a descriptive study of ISS conducted in the emergency department at a free-standing, academic pediatric institution. We designed two scenarios, one for an eligible and ineligible patient, to allow care teams to complete all study procedures. All study training was completed before the first ISS. Participants included physicians, nurses, patient care assistants, paramedics, research coordinators, and pharmacists. Ten-minute simulations were followed by 10-minute debriefings, led by trained facilitators using a standard template. Data on threats to enrollment, protocol adherence, and patient safety were recorded. Mitigation strategies were developed by the study team and local experts in ISS.

Results

Ten of 18 planned simulations were conducted. Seven of 10 completed simulations were study eligible patients, with 73 total participants. Nine threats to enrollment and five to protocol adherence were identified. Five of 14 were also threats to patient safety. Mitigation strategies included creation of decision aid tools, targeted education during debriefings, adapting study material for use, and revision of status epilepticus treatment algorithm.

Conclusions

The addition of ISS to standard preparation for a multicenter clinical trial facilitated the identification and mitigation of threats to study participation and patient safety.
Fish in habitats with higher motorboat disturbance show reduced sensitivity to motorboat noise
Authors: Harding Harry R. , Gordon Timothy A. C. , Hsuan Rachel E. , Mackaness Alex C. E. , Radford Andrew N. , Simpson Stephen D.
Published: October 2018

Anthropogenic noise can negatively impact many taxa worldwide. It is possible that in noisy, high-disturbance environments, the range and severity of impacts could diminish over time, but the influence of previous disturbance remains untested in natural conditions. This study demonstrates the effects of motorboat noise on the physiology of an endemic cichlid fish in Lake Malawi. Exposure to motorboats (driven 20–100 m from fish) and loudspeaker playback of motorboat noise both elevated the oxygen-consumption rate at a single lower-disturbance site, characterized by low historic and current motorboat activity. Repeating this assay at further lower-disturbance sites revealed a consistent effect of elevated oxygen consumption in response to motorboat disturbance. However, when similar trials were repeated at four higher-disturbance sites, no effect of motorboat exposure was detected. These results demonstrate that disturbance history can affect local population responses to noise. Action regarding noise pollution should consider the past, as well as the present, when planning for the future.
Lessons from pressure denaturation of proteins
Authors: Roche Julien , Royer Catherine A.
Published: October 2018

Although it is now relatively well understood how sequence defines and impacts global protein stability in specific structural contexts, the question of how sequence modulates the configurational landscape of proteins remains to be defined. Protein configurational equilibria are generally characterized by using various chemical denaturants or by changing temperature or pH. Another thermodynamic parameter which is less often used in such studies is high hydrostatic pressure. This review discusses the basis for pressure effects on protein structure and stability, and describes how the unique mechanisms of pressure-induced unfolding can provide unique insights into protein conformational landscapes.
Into the breach: how cells cope with wounds
Authors: Nakamura Mitsutoshi , Dominguez Andrew N. M. , Decker Jacob R. , Hull Alexander J. , Verboon Jeffrey M. , Parkhurst Susan M.
Published: October 2018

Repair of wounds to individual cells is crucial for organisms to survive daily physiological or environmental stresses, as well as pathogen assaults, which disrupt the plasma membrane. Sensing wounds, resealing membranes, closing wounds and remodelling plasma membrane/cortical cytoskeleton are four major steps that are essential to return cells to their pre-wounded states. This process relies on dynamic changes of the membrane/cytoskeleton that are indispensable for carrying out the repairs within tens of minutes. Studies from different cell wound repair models over the last two decades have revealed that the molecular mechanisms of single cell wound repair are very diverse and dependent on wound type, size, and/or species. Interestingly, different repair models have been shown to use similar proteins to achieve the same end result, albeit sometimes by distinctive mechanisms. Recent studies using cutting edge microscopy and molecular techniques are shedding new light on the molecular mechanisms during cellular wound repair. Here, we describe what is currently known about the mechanisms underlying this repair process. In addition, we discuss how the study of cellular wound repair—a powerful and inducible model—can contribute to our understanding of other fundamental biological processes such as cytokinesis, cell migration, cancer metastasis and human diseases.
Greater loss of female embryos during human pregnancy: A novel mechanism
Authors: Mulley John F
Published: October 2018

Given an equal sex ratio at conception, we can only explain the excess of human males at birth by greater loss of females during pregnancy. I propose that the bias against females during human development is the result of a greater degree of genetic and metabolic “differentness” between female embryos and maternal tissues than for similarly aged males, and that successful implantation and placentation represents a threshold dichotomy, where the acceptance threshold shifts depending on maternal condition, especially stress. Right and left ovaries are not equal, and neither are the eggs and follicular fluid that they produce, and I further hypothesise that during times of stress, the implantation threshold is shifted sufficiently to favour survival of females, most likely those originating from the right ovary, and that this, rather than simply a greater loss of males, explains at least some of the variability in the human sex ratio at birth.
Toward single particle reconstruction without particle picking: Breaking the detection limit
Authors: Bendory Tamir , Boumal Nicolas , Leeb William , Levin Eitan , Singer Amit
Published: October 2018

Single-particle cryo-electron microscopy (cryo-EM) has recently joined X-ray crystallography and NMR spectroscopy as a high-resolution structural method for biological macromolecules. In a cryo-EM experiment, the microscope produces images called micrographs. Projections of the molecule of interest are embedded in the micrographs at unknown locations, and under unknown viewing directions. Standard imaging techniques first locate these projections (detection) and then reconstruct the 3-D structure from them. Unfortunately, high noise levels hinder detection. When reliable detection is rendered impossible, the standard techniques fail. This is a problem especially for small molecules, which can be particularly hard to detect. In this paper, we propose a radically different approach: we contend that the structure could, in principle, be reconstructed directly from the micrographs, without intermediate detection. As a result, even small molecules should be within reach for cryo-EM. To support this claim, we setup a simplified mathematical model and demonstrate how our autocorrelation analysis technique allows to go directly from the micrographs to the sought signals. This involves only one pass over the micrographs, which is desirable for large experiments. We show numerical results and discuss challenges that lay ahead to turn this proof-of-concept into a competitive alternative to state-of-the-art algorithms.
Layer-specific ultra-high field 7T fMRI showing that threat anticipation is mediated by the pulvinar input to the superficial layers of primary visual cortex (V1)
Authors: Koizumi Ai , Zhan Minye , Ban Hiroshi , Kida Ikuhiro , Martino Federico de , Gelder Beatrice de , Amano Kaoru
Published: October 2018

The perceptual system gives priority to threat-relevant signals with survival value. Its mechanism may not only include the processing initiated in the presence of threat signals but also in the mere anticipation of such signals. Here, we show that the pulvinar modulates activity in the early visual cortex (V1) specifically in threat anticipation. Using ultra-high-field 7T fMRI, we examined the layer-specific interaction between V1 and the pulvinar, while taking advantage of the fact that the directionality of such interaction is anatomically constrained in specific V1 layers. Only in anticipation of a fearful face target, but not of a control happy face target, was false perception of anticipated-yet-unpresented target face accompanied by stronger activity in the V1 superficial-cortical-depth (layers 1-3), which was preceded by pre-target-onset pulvinar activity. The pulvinar may contribute to the visual processing initiated in the anticipation of threat, and play an important role in anxiety.
The TPX-Like protein TPXL3, but not TPX2, is the primary activator of α Aurora kinases and is essential for embryogenesis in Arabidopsis
Authors: Boruc Joanna , Deng Xingguang , Mylle Evelien , Besbrugge Nienke , Durme Matthias Van , Demidov Dmitri , Tomaštíková Eva Dvořák , Tan Tong-Reen Connie , Vandorpe Michaël , Eeckhout Dominique , Beeckman Tom , Nowack Moritz , Jaeger Geert De , Lin Honghui , Liu Bo , Damme Daniël Van
Published: October 2018

Aurora kinases are key regulators of mitosis. Multicellular eukaryotes generally possess two functionally diverged types. In plants like Arabidopsis, these are termed α versus β Auroras. As the functional specification of Aurora kinases is determined by their specific interaction partners, we initiated interactomics analyses using both α Aurora kinases (AUR1 and AUR2). Proteomics results revealed the TPX2-Like proteins 2 and 3 (TPXL2/3) prominently associating with α Auroras, as did the conserved TPX2 to a lower degree. Like TPX2, TPXL2 and TPXL3 strongly activated AUR1 kinase but exhibited cell cycle-dependent localization differences on microtubule arrays. The separate functions of TPX2 and TPXL2/3 were also suggested by their different influences on AUR1 localization upon ectopic expressions. Furthermore, genetic analyses disclosed that TPXL3, but not TPX2 and TPXL2, acts non-redundantly to secure proper embryo development. In contrast to vertebrates, plants expanded the TPX2 family for both redundant and unique functions among its members.
Genomic insights into evolutionary journey of the porcine endogenous retroviruses
Authors: Chen Yicong , Chen Mingyue , Duan Xiaoyan , Cui Jie
Published: October 2018

Background

Xenotransplantation may overcome significant shortage of human allotransplant. Porcine organs are considered favorable for xenotransplantation duo to similar size and function to human organ. However, porcine endogenous retroviruses (PERVs) are potential infectious agents during xenotransplantation as they are able to infect and horizontally transfer among human cells. Furthermore, PERVs can be endogenized in pig genomes and are transmitted genetically in a Mendelian fashion. Here, we depict a complex evolutionary history of modern PERVs.

Results

Wein silicomined 142 mammalian genomes and 14 pig genomes. This led to the documentation of 185 PERVs and a new viral cluster. Large-scale genomic alterations were found in most PERVs including many insertion-deletion events and which are suggestive of ancient origins, and pig genomes have been shaped by PERV-mediated genomic rearrangement during evolution. Notably, we found that lesser Egyptian jerboa and rock hyrax harbor ancestral PERV-related elements indicative of ancient cross-species transmission events from none-porcine species to pigs. A comprehensive analysis of these viral “fossils” suggested that recombination among none-porcine endogenous retroviruses led to the origination of PERVs.

Conclusion

For the first time, using large scale genomic mining, we decipher a complex evolutionary history for the PERVs. These new findings help us to understand the past of PERVs which pose the potential risk in clinical trials of xenotransplantation and provide novel insights into the origin and evolution of a human-infecting pathogen.
Presynaptic Endoplasmic Reticulum Contributes Crucially to Short-term Plasticity in Small Hippocampal Synapses
Authors: Singh Nishant , Bartol Thomas , Levine Herbert , Sejnowski Terrence , Nadkarni Suhita
Published: October 2018

Short-term plasticity (STP) of the presynaptic terminal maintains a brief history of activity experienced by the synapse that may otherwise remain unseen by the postsynaptic neuron. These synaptic changes are primarily regulated by calcium dynamics in the presynaptic terminal. A rapid increase in intracellular calcium is initiated by the opening of voltage-dependent calcium channels in response to depolarization, the main source of calcium required for vesicle fusion. Separately, electron-microscopic studies of hippocampal CA3-CA1 synapses reveal the strong presence of endoplasmic reticulum (ER) in all presynaptic terminals. However, the precise role of the ER in modifying STP at the presynaptic terminal remains unexplored. To investigate the contribution of ER in modulating calcium dynamics in small hippocampal boutons, we performed in silico experiments in a physiologically-realistic canonical synaptic geometry based on reconstructions of CA3-CA1 Schaffer collaterals in the rat hippocampus. The model predicts that presynaptic calcium stores are critical in generating the observed paired-pulse ratio (PPR) of normal CA3-CA1 synapses. In control synapses with intact ER, SERCA pumps act as additional calcium buffers, lowering the intrinsic release probability of vesicle release and increasing PPR. In addition, the presence of ER allows ongoing activity to trigger calcium influx from the presynaptic ER via ryanodine receptors (RyRs) and inositol trisphosphate receptors (IP3Rs). Intracellular stores and their associated machinery also allows a synapse with a low release probability to operate more reliably due to attenuation of calcium fluctuations. Finally, blocking ER activity in the presynaptic terminal mimics the pathological state of a low facilitating synapse characterized in animal models of Alzheimer’s disease, and underscores the critical role played by presynaptic stores in normal function.
Genetic and behavioural requirements for structural brain plasticity
Authors: Vousden Dulcie A , Friesen Alexander , Wen Xianglan , Qiu Lily R , O’Toole Nicholas , Darwin Benjamin C , Noakes Leigh Spencer , Grand Rylan Allemang , Diorio Josie , Frankland Paul W , Josselyn Sheena A , Nieman Brian J , Meaney Michael , Zhang Tie-Yuan , Lerch Jason P
Published: October 2018

1

Human MRI studies show that experience can lead to changes in the volume of task-specific brain regions; however, the behavioural and molecular processes driving these changes remain poorly understood. Here, we used in-vivo mouse MRI and RNA sequencing to investigate the neuroanatomical and transcriptional changes induced by environmental enrichment, exercise, and social interaction. Additionally, we asked whether the volume changes require CREB, a transcription factor critical for memory formation and neuronal plasticity. Enrichment rapidly increased cortical and hippocampal volume, and these effects were not attributable to exercise or social interaction. Instead, they likely arise from learning and sensorimotor experience. Nevertheless, the volume changes were not attenuated in mice with memory impairments caused by loss of CREB, indicating that these effects are driven by processes distinct from this canonical learning and memory pathway. Finally, within brain regions that underwent volume changes, enrichment increased the expression of genes associated with axonogenesis, dendritic spine development, synapse structural plasticity, and neurogenesis, suggesting these processes underlie the volume changes detected with MRI.