bluuebunny/crossref_metadata_2025 huggingface dataset:
SummaryAUC: a tool for evaluating the performance of polygenic risk prediction models in validation datasets with only summary level statistics
Authors: Song Lei , Liu Aiyi , Shi Jianxin ,   Molecular Genetics of Schizophrenia Consortium, Gejman P V , Sanders A R , Duan J , Cloninger C R , Svrakic D M , Buccola N G , Levinson D F , Mowry B J , Freedman R , Olincy A , Amin F , Black D W , Silverman J M , Byerley W F
Published: March 2019

Motivation

Polygenic risk score (PRS) methods based on genome-wide association studies (GWAS) have a potential for predicting the risk of developing complex diseases and are expected to become more accurate with larger training datasets and innovative statistical methods. The area under the ROC curve (AUC) is often used to evaluate the performance of PRSs, which requires individual genotypic and phenotypic data in an independent GWAS validation dataset. We are motivated to develop methods for approximating AUC of PRSs based on the summary level data of the validation dataset, which will greatly facilitate the development of PRS models for complex diseases.

Results

We develop statistical methods and an R package SummaryAUC for approximating the AUC and its variance of a PRS when only the summary level data of the validation dataset are available. SummaryAUC can be applied to PRSs with SNPs either genotyped or imputed in the validation dataset. We examined the performance of SummaryAUC using a large-scale GWAS of schizophrenia. SummaryAUC provides accurate approximations to AUCs and their variances. The bias of AUC is typically <0.5% in most analyses. SummaryAUC cannot be applied to PRSs that use all SNPs in the genome because it is computationally prohibitive.

Availability and implementation

https://github.com/lsncibb/SummaryAUC.

Supplementary information

Supplementary data are available at Bioinformatics online.
Simulation-assisted machine learning
Authors: Deist Timo M , Patti Andrew , Wang Zhaoqi , Krane David , Sorenson Taylor , Craft David
Published: March 2019

Motivation

In a predictive modeling setting, if sufficient details of the system behavior are known, one can build and use a simulation for making predictions. When sufficient system details are not known, one typically turns to machine learning, which builds a black-box model of the system using a large dataset of input sample features and outputs. We consider a setting which is between these two extremes: some details of the system mechanics are known but not enough for creating simulations that can be used to make high quality predictions. In this context we propose using approximate simulations to build a kernel for use in kernelized machine learning methods, such as support vector machines. The results of multiple simulations (under various uncertainty scenarios) are used to compute similarity measures between every pair of samples: sample pairs are given a high similarity score if they behave similarly under a wide range of simulation parameters. These similarity values, rather than the original high dimensional feature data, are used to build the kernel.

Results

We demonstrate and explore the simulation-based kernel (SimKern) concept using four synthetic complex systems—three biologically inspired models and one network flow optimization model. We show that, when the number of training samples is small compared to the number of features, the SimKern approach dominates over no-prior-knowledge methods. This approach should be applicable in all disciplines where predictive models are sought and informative yet approximate simulations are available.

Availability and implementation

The Python SimKern software, the demonstration models (in MATLAB, R), and the datasets are available at https://github.com/davidcraft/SimKern.

Supplementary information

Supplementary data are available at Bioinformatics online.
Incidence and Trends in Immune Reconstitution Inflammatory Syndrome Associated With Histoplasma capsulatum Among People Living With Human Immunodeficiency Virus: A 20-Year Case Series and Literature Review
Authors: Melzani Alessia , de Reynal de Saint Michel Regis , Ntab Balthazar , Djossou Felix , Epelboin Loic , Nacher Mathieu , Blanchet Denis , Demar Magalie , Couppie Pierre , Adenis Antoine
Published: March 2019

Background

Histoplasmosis is among the main acquired immunodeficiency syndrome (AIDS)–defining conditions in endemic areas. Although histoplasmosis has a worldwide distribution, histoplasmosis-associated immune reconstitution inflammatory syndrome (IRIS) in people living with human immunodeficiency virus (PLHIV) is rarely reported.

This study aimed to describe the incidence and features of histoplasmosis-associated IRIS in a cohort of PLHIV.

Methods

A retrospective multicenter study was conducted in French Guiana from 1 January 1997 to 30 September 2017. The target population was represented by PLHIV who presented an episode of histoplasmosis within 6 months after antiretroviral therapy initiation. We used a consensual IRIS case definition, submitted to the agreement of 2 experts. Each case was described using a standardized questionnaire, and all patients gave informed consent.

Results

Twenty-two cases of histoplasmosis-associated IRIS were included (14 infectious/unmasking and 8 paradoxical), with an overall incidence rate of 0.74 cases per 1000 HIV-infected person-years (95% confidence interval, 0.43–1.05). Mean age was 40.5 years. The ratio of males to females was 1:4. Median time to IRIS was 11 days (interquartile range 7–40 days) after antiretroviral therapy initiation. The main clinical presentation was fever, without any specific pattern, and disseminated disease. We reported 2 severe cases and partial or complete recovery at 1 month was the rule. Twenty-two cases were identified in the literature with similar characteristics.

Conclusions

Histoplasmosis-associated IRIS incidence was low but generated significant morbidity in PLHIV. In endemic areas, screening for latent or subclinical histoplasmosis should be implemented before antiretroviral therapy initiation.
Butyrate Does Not Protect Against Inflammation-induced Loss of Epithelial Barrier Function and Cytokine Production in Primary Cell Monolayers From Patients With Ulcerative Colitis
Authors: Vancamelbeke Maaike , Laeremans Thessa , Vanhove Wiebe , Arnauts Kaline , Ramalho Anabela Santo , Farré Ricard , Cleynen Isabelle , Ferrante Marc , Vermeire Séverine
Published: March 2019

Background and Aims

In vitro studies using immortalised cancer cell lines showed that butyrate has an overall positive effect on epithelial barrier integrity, but the physiological relevance of cancer cell lines is limited. We developed epithelial monolayers from human tissue samples of patients with ulcerative colitis [UC] to assess the effect of butyrate on epithelial barrier function.

Methods

A protocol to establish monolayers from primary epithelial cells of UC patients [n = 10] and non-UC controls [n = 10] was optimised. The monolayers were treated with 8 mM sodium butyrate ± tumour necrosis factor alpha [TNFα] and type II interferon [IFNγ] for 48 h. Changes in transepithelial electrical resistance were monitored. Barrier gene expression levels were measured. Inflammatory proteins in the supernatant of the cells were quantified with OLINK.

Results

We demonstrated that primary monolayer cultures can be grown within 1 week of culture with robust resistance values and polarised tight junction expression. Butyrate treatment of the cultures increased resistance but was detrimental in combination with TNFα and IFNγ. The combined treatment further induced even higher IL8 mRNA and inflammatory protein secretion than for the inflammatory mediators alone. The observed effects were similar in cultures from patients and non-UC controls, suggesting that there were no patient-specific responses responsible for these findings.

Conclusions

We found that butyrate does not protect against inflammation-induced barrier dysfunction and even worsens its effects in primary epithelial monolayers of UC patients and controls. The basic mechanisms of butyrate should therefore be reconsidered in future studies, in particular in patients with active inflammation and pre-existing barrier defects as is known for UC.
Mechanistic target of rapamycin signaling in mouse models of accelerated aging
Authors: Lee Jin Young , Kennedy Brian K , Liao Chen-Yu
Published: March 2019

The mechanistic target of rapamycin (mTOR) is an essential nutrient-sensing kinase that integrates and regulates a number of fundamental cellular processes required for cell growth, cell motility, translation, metabolism, and autophagy. mTOR signaling has been implicated in the progression of many human diseases, and its dysregulation has been reported in several pathological processes, especially in age-related human diseases and mouse models of accelerated aging. In addition, many studies have demonstrated that the regulation of mTOR activity has a beneficial effect on longevity in several mouse models of aging. However, not all mouse models of accelerated aging show positive effects on aging-associated phenotypes in response to targeting mTOR signaling. Here, we review the effects of interventions that modulate mTOR signaling on aging-related phenotypes in different mouse models of accelerated aging and discuss their implications with respect to aging and aging-related disorders.
Amyotrophic lateral sclerosis-associated TDP-43 mutation Q331K prevents nuclear translocation of XRCC4-DNA ligase 4 complex and is linked to genome damage-mediated neuronal apoptosis
Authors: Guerrero Erika N , Mitra Joy , Wang Haibo , Rangaswamy Suganya , Hegde Pavana M , Basu Priyadarshini , Rao K S , Hegde Muralidhar L
Published: March 2019

Dominant mutations in the RNA/DNA-binding protein TDP-43 have been linked to amyotrophic lateral sclerosis (ALS). Here, we screened genomic DNA extracted from spinal cord specimens of sporadic ALS patients for mutations in the TARDBP gene and identified a patient specimen with previously reported Q331K mutation. The patient spinal cord tissue with Q331K mutation showed accumulation of higher levels of DNA strand breaks and the DNA double-strand break (DSB) marker γH2AX, compared to age-matched controls, suggesting a role of the Q331K mutation in genome-damage accumulation. Using conditional SH-SY5Y lines ectopically expressing wild-type (WT) or Q331K-mutant TDP-43, we confirmed the increased cytosolic sequestration of the poly-ubiquitinated and aggregated form of mutant TDP-43, which correlated with increased genomic DNA strand breaks, activation of the DNA damage response factors phospho-ataxia-telangiectasia mutated (ATM), phospho-53BP1, γH2AX and neuronal apoptosis. We recently reported the involvement of WT TDP-43 in non-homologous end joining (NHEJ)-mediated DSB repair, where it acts as a scaffold for the recruitment of XRCC4-DNA ligase 4 complex. Here, the mutant TDP-43, due to its reduced interaction and enhanced cytosolic mislocalization, prevented the nuclear translocation of XRCC4-DNA ligase 4. Consistently, the mutant cells showed significantly reduced DNA strand break sealing activity and were sensitized to DNA-damaging drugs. In addition, the mutant cells showed elevated levels of reactive oxygen species, suggesting both dominant negative and loss-of-function effects of the mutation. Together, our study uncovered an association of sporadic Q331K mutation with persistent genome damage accumulation due to both damage induction and repair defects.
Rare variants in MYH15 modify amyotrophic lateral sclerosis risk
Authors: Kim Hyerim , Lim Junghwa , Bao Han , Jiao Bin , Canon Se Min , Epstein Michael P , Xu Keqin , Jiang Jie , Parameswaran Janani , Li Yingjie , Moberg Kenneth H , Landers John E , Fournier Christina , Allen Emily G , Glass Jonathan D , Wingo Thomas S , Jin Peng
Published: March 2019

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive muscular atrophy and respiratory failure. The G4C2 repeat expansion in the C9orf72 gene is the most prevalent genetic risk for ALS. Mutation carriers (C9ALS) display variability in phenotypes such as age-at-onset and duration, suggesting the existence of additional genetic factors. Here we introduce a three-step gene discovery strategy to identify genetic factors modifying the risk of both C9ALS and sporadic ALS (sALS) using limited samples. We first identified 135 candidate genetic modifiers of C9ALS using whole-genome sequencing (WGS) of extreme C9ALS cases diagnosed ~30 years apart. We then performed an unbiased genetic screen using a Drosophila model of the G4C2 repeat expansion with the genes identified from WGS analysis. This genetic screen identified the novel genetic interaction between G4C2 repeat-associated toxicity and 18 genetic factors, suggesting their potential association with C9ALS risk. We went on to test if 14 out of the 18 genes, those which were not known to be risk factors for ALS previously, are also associated with ALS risk in sALS cases. Gene-based-statistical analyses of targeted resequencing and WGS were performed. These analyses together reveal that rare variants in MYH15 represent a likely genetic risk factor for ALS. Furthermore, we show that MYH15 could modulate the toxicity of dipeptides produced from expanded G4C2 repeat. Our study presented here demonstrates the power of combining WGS with fly genetics to facilitate the discovery of fundamental genetic components of complex traits with a limited number of samples.
Externalized conductor of a Kentrox lead and an unexpected insulation failure
Authors: Eulert-Grehn Jaime-Jürgen , Falk Volkmar , Nazari-Shafti Mir Timo , Starck Christoph
Published: March 2019

Cardiac resynchronization therapy-defibrillator device upgrades may represent a challenging scenario, especially because unexpected findings can increase procedure difficulty. One such unexpected finding represents insulation failure with unremarkable device interrogation. Insulation failure due to an externalized conductor of an implantable cardiac defibrillator-lead has been recently described for the Kentrox lead (Biotronik). Another challenging aspect of device upgrades is the presence of venous thrombosis as in this case. Here, we report an inside-out abrasion of a Kentrox lead, an unexpected second insulation failure found during pocket revision and the successful recanalization in a patient with known left subclavian vein thrombosis.
Infinite Geodesics of Sub-Finsler Distances in Heisenberg Groups
Authors: Balogh Zoltán M , Calogero Andrea
Published: March 2019

We consider Heisenberg groups equipped with a sub-Finsler metric. Using methods of optimal control theory we prove that in this geometric setting the infinite geodesics are horizontal lines under the assumption that the sub-Finsler metric is defined by a strictly convex norm. This answers a question posed in [8] and has applications in the characterization of isometric embeddings into Heisenberg groups.
Control of the HIV-1 Load Varies by Viral Subtype in a Large Cohort of African Adults With Incident HIV-1 Infection
Authors: Price Matt A , Rida Wasima , Kilembe William , Karita Etienne , Inambao Mubiana , Ruzagira Eugene , Kamali Anatoli , Sanders Eduard J , Anzala Omu , Hunter Eric , Allen Susan , Edward Vinodh A , Wall Kristin M , Tang Jianming , Fast Patricia E , Kaleebu Pontiano , Lakhi Shabir , Mutua Gaudensia , Bekker Linda Gail , Abu-Baker Ggayi , Tichacek Amanda , Chetty Paramesh , Latka Mary H , Maenetje Pholo , Makkan Heeran , Kibengo Freddie , Priddy Fran , Gilmour Jill
Published: March 2019

Few human immunodeficiency virus (HIV)–infected persons can maintain low viral levels without therapeutic intervention. We evaluate predictors of spontaneous control of the viral load (hereafter, “viral control”) in a prospective cohort of African adults shortly after HIV infection. Viral control was defined as ≥2 consecutively measured viral loads (VLs) of ≤10 000 copies/mL after the estimated date of infection, followed by at least 4 subsequent measurements for which the VL in at least 75% was ≤10 000 copies/mL in the absence of ART. Multivariable logistic regression characterized predictors of viral control. Of 590 eligible volunteers, 107 (18.1%) experienced viral control, of whom 25 (4.2%) maintained a VL of 51–2000 copies/mL, and 5 (0.8%) sustained a VL of ≤50 copies/mL. The median ART-free follow-up time was 3.3 years (range, 0.3–9.7 years). Factors independently associated with control were HIV-1 subtype A (reference, subtype C; adjusted odds ratio [aOR], 2.1 [95% confidence interval {CI}, 1.3–3.5]), female sex (reference, male sex; aOR, 1.8 [95% CI, 1.1–2.8]), and having HLA class I variant allele B*57 (reference, not having this allele; aOR, 1.9 [95% CI, 1.0–3.6]) in a multivariable model that also controlled for age at the time of infection and baseline CD4+ T-cell count. We observed strong associations between infecting HIV-1 subtype, HLA type, and sex on viral control in this cohort. HIV-1 subtype is important to consider when testing and designing new therapeutic and prevention technologies, including vaccines.
Disrupting Membrane Adaptation Restores In Vivo Efficacy of Antibiotics Against Multidrug-Resistant Enterococci and Potentiates Killing by Human Neutrophils
Authors: Rincon Sandra , Panesso Diana , Miller William R , Singh Kavindra V , Cruz Melissa R , Khan Ayesha , Dinh An Q , Diaz Lorena , Rios Rafael , Shamoo Yousif , Reyes Jinnethe , Tran Truc T , Garsin Danielle A , Arias Cesar A
Published: March 2019

Daptomycin resistance in enterococci is often mediated by the LiaFSR system, which orchestrates the cell membrane stress response. Activation of LiaFSR through the response regulator LiaR generates major changes in cell membrane function and architecture (membrane adaptive response), permitting the organism to survive the antibiotic attack. Here, using a laboratory strain of Enterococcus faecalis, we developed a novel Caenorhabditis elegans model of daptomycin therapy and showed that disrupting LiaR-mediated cell membrane adaptation restores the in vivo activity of daptomycin. The LiaR effect was also seen in a clinical strain of daptomycin-resistant Enterococcus faecium, using a murine model of peritonitis. Furthermore, alteration of the cell membrane response increased the ability of human polymorphonuclear neutrophils to readily clear both E. faecalis and multidrug-resistant E. faecium. Our results provide proof of concept that targeting the cell membrane adaptive response restores the in vivo activity of antibiotics, prevents resistance, and enhances the ability of the innate immune system to kill infecting bacteria.
Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants
Authors: Jacqz-Aigrain Evelyne , Leroux Stéphanie , Thomson Alison H , Allegaert Karel , Capparelli Edmund V , Biran Valérie , Simon Nicolas , Meibohm Bernd , Lo Yoke-Lin , Marques Remedios , Peris José-Esteban , Lutsar Irja , Saito Jumpei , Nakamura Hidefumi , van den Anker Johannes N , Sharland Mike , Zhao Wei
Published: March 2019

Objectives

In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates.

Methods

A ‘meta-model’ with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0–24 of 400 mg·h/L at steady-state in at least 80% of neonates.

Results

A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <35 weeks PMA and 15 mg/kg q8h if ≥35 weeks PMA) achieved the AUC0–24 target earlier than a standard ‘Blue Book’ dosage regimen in >89% of the treated patients.

Conclusions

The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc.
Whole-genome analysis of extraintestinal pathogenic Escherichia coli (ExPEC) MDR ST73 and ST127 isolated from endangered southern resident killer whales (Orcinus orca)
Authors: Melendez Daira , Roberts Marilyn C , Greninger Alexander L , Weissman Scott , No David , Rabinowitz Peter , Wasser Samuel
Published: March 2019

Background

Limited studies have investigated the microbial diversity of wild marine mammals.

Objectives

This study characterized Escherichia coli isolates collected from fresh faecal samples of endangered southern resident killer whales (Orcinus orca) located by detection dogs.

Methods

WGS of each strain was done to determine ST (using MLST), clonotype (C:H), antimicrobial resistance and virulence profile. Conjugation experiments were done to determine the mobility of the tet(B) tetracycline resistance gene.

Results

All isolates belonged to extraintestinal pathogenic E. coli (ExPEC) clonal lineages ST73 (8/9) and ST127 (1/9), often associated with human community-acquired urinary tract disease. Clonotyping using fumC and fimH alleles showed divergence in clonal lineages, with ST73 isolates belonging to the C24:H10 clade and the ST127 isolate belonging to C14:H2. The eight ST73 isolates carried multiple acquired antibiotic resistance genes, including aadA1, sul1 and tet(B), encoding aminoglycoside, sulphonamide and tetracycline resistance, respectively. Conjugative transfer of the resistance gene tet(B) was observed for three of the eight isolates. ST127 did not carry any of these acquired resistance genes. Virulence-associated genes identified included those encoding adhesins (iha, papC, sfaS), toxins (sat, vat, pic, hlyA, cnf1), siderophores (iutA, fyuA, iroN, ireA), serum survival/protectins (iss, ompT), capsule (kpsM) and pathogenicity island marker (malX).

Conclusions

Orca whales can carry antibiotic-resistant potentially pathogenic strains of E. coli. Possible sources include contamination of the whale’s environment and/or food. It is unknown whether these isolates cause disease in southern resident killer whales, which could contribute to the ongoing decline of this critically endangered population.
Interobserver variability of 3.0-tesla and 1.5-tesla magnetic resonance imaging/computed tomography fusion image–based post-implant dosimetry of prostate brachytherapy
Authors: Watanabe Kenta , Katayama Norihisa , Katsui Kuniaki , Matsushita Toshi , Takamoto Atsushi , Ihara Hiroki , Nasu Yasutomo , Takemoto Mitsuhiro , Kuroda Masahiro , Kanazawa Susumu
Published: March 2019

This study aimed to compare the interobserver variabilities in magnetic resonance imaging (MRI)/computed tomography (CT) fusion image–based post-implant dosimetry of permanent prostate brachytherapy (PPB) between 1.5-T and 3.0-T MRI. The study included 60 patients. Of these patients, 30 underwent 1.5-T MRI and CT 30 days after seed implantation (1.5-T group), and 30 underwent 3.0-T MRI and CT 30 days after seed implantation (3.0-T group). All patients received PPB alone. Two radiation oncologists performed MRI/CT fusion image–based post-implant dosimetry, and the interobserver variabilities of dose–volume histogram (DVH) parameters [dose (Gy) received by 90% of the prostate volume (prostate D90)], percentage of the prostate volume receiving at least the full prescribed dose (prostate V100), percentage of the prostate volume receiving at least 150% of the prescribed dose (prostate V150), dose (Gy) received by 5% of the urethral volume (urethral D5) and the urethral volume receiving at least 150% of the prescribed dose (urethral V150)] were retrospectively estimated using the paired Student’s t test and Pearson’s correlation coefficient. The Pearson’s correlation coefficients of all DVH parameters were higher in the 3.0-T group than in the 1.5-T group (1.5-T vs 3.0-T: prostate D90, 0.65 vs 0.93; prostate V100, 0.62 vs 0.82; prostate V150, 0.97 vs 0.98; urethral D5, 0.92 vs 0.93; and urethral V150, 0.88 vs 0.93). In the paired Student’s t test, no significant differences were observed in any of the DVH parameters between the two radiation oncologists in the 3.0-T group (0.068 ≤ P ≤ 0.842); however, significant differences were observed in prostate D90 (P = 0.004), prostate V100 (P = 0.011) and prostate V150 (P = 0.002) between the oncologists in the 1.5-T group. The interobserver variability of DVH parameters in the MRI/CT fusion image–based post-implant dosimetry analysis of brachytherapy was lower with 3.0-T MRI than with 1.5-T MRI.
Rice aquaporin PIP1;3 and harpin Hpa1 of bacterial blight pathogen cooperate in a type III effector translocation
Authors: Li Ping , Zhang Liyuan , Mo Xuyan , Ji Hongtao , Bian Huijie , Hu Yiqun , Majid Taha , Long Juying , Pang Hao , Tao Yuan , Ma Jinbiao , Dong Hansong
Published: March 2019

Varieties of Gram-negative bacterial pathogens infect their eukaryotic hosts by deploying the type III translocon to deliver effector proteins into the cytosol of eukaryotic cells in which effectors execute their pathological functions. The translocon is hypothetically assembled by bacterial translocators in association with the assumed receptors situated on eukaryotic plasma membranes. This hypothesis is partially verified in the present study with genetic, biochemical, and pathological evidence for the role of a rice aquaporin, plasma membrane intrinsic protein PIP1;3, in the cytosolic import of the transcription activator-like effector PthXo1 from the bacterial blight pathogen. PIP1;3 interacts with the bacterial translocator Hpa1 at rice plasma membranes to control PthXo1 translocation from cells of a well-characterized strain of the bacterial blight pathogen into the cytosol of cells of a susceptible rice variety. An extracellular loop sequence of PIP1;3 and the α-helix motif of Hpa1 determine both the molecular interaction and its consequences with respect to the effector translocation and the bacterial virulence on the susceptible rice variety. Overall, these results provide multiple experimental avenues to support the hypothesis that interactions between bacterial translocators and their interactors at the target membrane are essential for bacterial effector translocation.
Sulfate transport systems in plants: functional diversity and molecular mechanisms underlying regulatory coordination
Authors: Takahashi Hideki
Published: March 2019

Sulfate transporters are integral membrane proteins controlling the flux of sulfate (SO42–) entering the cells and subcellular compartments across the membrane lipid bilayers. Sulfate uptake is a dynamic biological process that occurs in multiple cell layers and organs in plants. In vascular plants, sulfate ions are taken up from the soil environment to the outermost cell layers of roots and horizontally transferred to the vascular tissues for further distribution to distant organs. The amount of sulfate ions being metabolized in the cytosol and chloroplast/plastid or temporarily stored in the vacuole depends on expression levels and functionalities of sulfate transporters bound specifically to the plasma membrane, chloroplast/plastid envelopes, and tonoplast membrane. The entire system for sulfate homeostasis, therefore, requires different types of sulfate transporters to be expressed and coordinately regulated in specific organs, cell types, and subcellular compartments. Transcriptional and post-transcriptional regulatory mechanisms control the expression levels and functions of sulfate transporters to optimize sulfate uptake and internal distribution in response to sulfate availability and demands for synthesis of organic sulfur metabolites. This review article provides an overview of sulfate transport systems and discusses their regulatory aspects investigated in the model plant species Arabidopsis thaliana.
An Assessment of Flight Surgeon Confidence to Perform En Route Care
Authors: Andicochea Chad T , Wilson James , Raetz Emily , Walrath Benjamin
Published: March 2019

Introduction

En Route Care (ERC) is often an ad hoc mission for the USN. In a review of 428 Navy patient transports, a Flight Surgeon (FS) was the sole provider or a member of crew in 118 of the transports. Naval FSs receive approximately 4 hours of didactic ERC training during their 24-week Naval FS course. Regardless, an FS may be caring for a critically ill patient in a helicopter. We conducted a survey to evaluate FS confidence in their ability to perform ERC and to establish their understanding of the training of Search and Rescue Medical Technicians (SMT).

Materials and Methods

A convenience sample of FSs completed a needs analysis survey as part of a process improvement project. Flight Surgeons surveyed were actively assigned or had been assigned within the past year to a squadron with Search and Rescue/MEDEVAC capabilities.

Results

A total of 25 surveys were completed. An average of 13 (range 0–100) patient transport missions were performed by the respondents. Twenty-five percent reported feeling confident in their ability to provide ERC without senior level direction, while 41% stated they would require direction. Nearly 70% of the FSs surveyed expressed “minimal” or less understanding of the training of the SMT.

Conclusions

Our survey results reveal most FSs are confident in neither their ability to perform ERC nor the ability of their hospital corpsman to provide care during patient movement.
Development and Implementation of U.S. Army Guidelines for Managing Soldiers at Risk of Suicide
Authors: Hoyt Tim , Repke Diana M
Published: March 2019

Objectives

Despite significant efforts in suicide prevention over the past several years, suicide rates in the U.S. Army remain largely unchanged. This paper describes a collaborative effort between line-unit leaders, medical personnel, and installation services to synchronize suicide risk identification and communication between these disparate entities.

Methods

Under the direction of the Installation Director of Psychological Health at Joint Base Lewis-McChord, a Behavioral Health Process Action Team was chartered to identify best practice and formulate policy for identifying and managing service members at risk for suicide.

Results

Compliance with the new policy reached 100% within 6 months of implementation, as measured by peer review of records. This installation policy was subsequently identified as a best practice and adopted Army-wide as the standard of practice.

Discussion

Knowledge transfer of research findings into policy and practice is crucial for suicide prevention. The current policy shows good integration of current research with practice in military settings.

Conclusions

Combined efforts in crafting policy for risk identification and communication resulted in a policy that was acceptable and feasible from the perspective of commanders and clinicians. Synchronization efforts between commanders, clinicians, and support services are crucial to ensure effective intervention to prevent suicide behavior.
Accelerating Psychological Health Research Findings into Clinical Practice Through the Practice-Based Implementation Network Model
Authors: Creason Alia H , Ruscio Aimee C , Tate Karyn E , McGraw Kate L
Published: March 2019

The benefits of new clinical research developments often take years to reach patients. As such, the Departments of Defense (DoD) and Veterans Affairs built the Practice-Based Implementation (PBI) Network as an infrastructure to facilitate more rapid translation of psychological health (PH) research into clinical practice changes to improve the quality of care for military and Veteran patients. To regularly identify research findings appropriate for enterprise implementation, the DoD PBI Network developed a model aligned with the Consolidated Framework for Implementation Research to select and pilot PH practice change. Within this model, practice change pilots were selected following a survey of field clinicians, a public call for proposals, annual meeting of implementation science subject matter experts, and final pilot selection by PH strategic leaders. These components facilitated commitment and engagement from Military Health System PH leadership, as well as clinicians, leading to increased stakeholder buy-in and efficiency with selecting and piloting PH practice change. The DoD PBI Network model has been refined for future PH research translation pilots. It serves as a first operational model for annual implementation of PH research findings in the DoD and may be of use to other entities engaged in practice change implementation.
Computational Modeling of Primary Blast Lung Injury: Implications for Ventilator Management
Authors: Herrmann Jacob , Tawhai Merryn H , Kaczka David W
Published: March 2019

Primary blast lung injury (PBLI) caused by exposure to high-intensity pressure waves is associated with parenchymal tissue injury and severe ventilation-perfusion mismatch. Although supportive ventilation is often required in patients with PBLI, maldistribution of gas flow in mechanically heterogeneous lungs may lead to further injury due to increased parenchymal strain and strain rate, which are difficult to predict in vivo. In this study, we developed a computational lung model with mechanical properties consistent with healthy and PBLI conditions. PBLI conditions were simulated with bilateral derecruitment and increased perihilar tissue stiffness. As a result of these tissue abnormalities, airway flow was heterogeneously distributed in the model under PBLI conditions, during both conventional mechanical ventilation (CMV) and high-frequency oscillatory ventilation. PBLI conditions resulted in over three-fold higher parenchymal strains compared to the healthy condition during CMV, with flow distributed according to regional tissue stiffness. During high-frequency oscillatory ventilation, flow distribution became increasingly heterogeneous and frequency-dependent. We conclude that the distribution and rate of parenchymal distension during mechanical ventilation depend on PBLI severity as well as ventilatory modality. These simulations may allow realistic assessment of the risks associated with ventilator-induced lung injury following PBLI, and facilitate the development of alternative lung-protective ventilation modalities.
Prehospital Interventions Performed in Afghanistan Between November 2009 and March 2014
Authors: Lairet Julio , Bebarta Vikhyat S , Maddry Joseph K , Reeves Lauren , Mora Alejandra , Blackbourne Lorne , Rasmussen Todd
Published: March 2019

Objective

Care provided to a casualty in the prehospital combat setting can influence subsequent medical interactions and impact patient outcomes; therefore, we aimed to describe the incidence of specific prehospital interventions (lifesaving interventions (LSIs)) performed during the resuscitation and transport of combat casualties.

Methods

We performed a prospective observational, IRB approved study between November 2009 and March 2014. Casualties were enrolled as they were cared for at nine U.S. military medical facilities in Afghanistan. Data were collected using a standardized collection form. Determination if a prehospital intervention was performed correctly, performed incorrectly, or was necessary but was not performed (missed LSIs) was made by the receiving facility’s medical provider.

Results

Two thousand one hundred and six patients met inclusion criteria. The mean age was 25 years and 98% were male. The most common mechanism of injury was explosion 57%. There were 236 airway interventions attempted, 183 chest procedures, 1,673 hemorrhage control, 1,698 vascular access, and 1,066 hypothermia preventions implemented. There were 142 incorrectly performed interventions and 360 were missed.

Conclusions

In our study, the most commonly performed prehospital LSI in a combat setting were for vascular access and hemorrhage control. The most common incorrectly performed and missed interventions were airway interventions and chest procedures respectively.
Preliminary Investigation of Civilian Clinician Perspectives & Just-in-Time Guidance for Tourniquet Use to “Stop the Bleed”
Authors: Lowndes Bethany , Law Katherine , Abdelrahman Amro , Prytz Erik , Jonson Carl-Oscar , Sztajnkrycer Matthew , Hawthorne Hunter , Franz Walter , Blocker Renaldo , Hallbeck M Susan
Published: March 2019

Objective

The American College of Surgeons (ACS) encourages clinicians to provide training to laypeople on tourniquet application. It is unclear whether clinicians are confident in their abilities and equipped with adequate knowledge, skills, and resources. This study aimed to determine surgical trainee knowledge and attitudes regarding tourniquet application and compare the effectiveness of instructions.

Methods

Thirty surgical trainees performed a tourniquet application simulation using a Combat Application Tourniquet and one of the three instructions sets developed by ACS, Department of Homeland Security, and the tourniquet manufacturer. Participants reported tourniquet knowledge, attitudes, and confidence and discussed the instructions. One instruction set was updated and compared to the original set with 20 new trainees.

Results

Participants with ACS instructions passed the greatest number of steps (p < 0.01) and completed the task significantly faster compared to those with manufacturer instructions (p < 0.01). Participants (80%) reported favorable views toward tourniquets but 30–60% did not align with to ACS tourniquet guidelines. Focus group participants suggested revisions to the ACS instructions. Comparing the original and revised version of these instructions resulted in no significant improvements.

Conclusions

ACS instructions provide guidance; however, improvements to tourniquet instruction are needed for success in controlling exsanguinating hemorrhage.
Effect of Sodium Lauryl Sulfate (SLS) on Primary Human Gingival Fibroblasts in an In Vitro Wound Healing Model
Authors: Chuang Augustine H , Bordlemay Justin , Goodin Jeremy L , McPherson James C
Published: March 2019

Objectives

Sodium lauryl sulfate (SLS) is a surfactant used to decrease the surface tension of water. Most commercially available dentifrices contain 0.5–2.0% SLS. This study investigated the potential effect of SLS on oral wound healing using primary human gingival fibroblasts (HGFs).

Methods

HGFs cells were grown in12-well culture plates in DMEM medium. A 3 mm wound was created on confluent HGFs. The cells were challenged with 0 (the control group), 0.01, 0.02, 0.03, 0.04, or 0.05% SLS-containing media once daily for 2 minutes. The cells were stained on day 0, 2, 4, 6 and 8. The percent of wound fill area was measured.

Results

On day 2, 4, 6, and 8, the wound fill of the control group (0% SLS) was 15, 35, 67 and 98%, respectively; at 0.01% SLS, it was 10, 20, 65 and 84%; at 0.02%, it was 7, 10, 15 and 25%; at 0.03% SLS, it was only 5% and 8% on day 2 and 4.

Conclusion

Our results showed a dose- and time-dependent inhibition on HGFs wound fill by SLS; however, future in vivo studies are needed to validate if our in vitro findings using SLS-free dentifrices to avoid the potential delay of wound healing.
On the Development of Interspecies Traumatic Brain Injury Correspondence Rules
Authors: Saunders Robert , Tan X Gary , Bagchi Amit
Published: March 2019

Traumatic brain injury analysis in human is exceedingly difficult due to the methods in which data can be collected, thus many researchers commonly implement animal surrogates. However, use of these surrogates is costly and restricted by ethical concerns and test logistics. Computational models and simulations do not have these constraints and can produce significant amounts of data in relatively short periods. This paper shows the development of a human head and neck model and a full body porcine model. Both models are developed from high-resolution CT and MRI scans and the latest low-to-high strain rate mechanical data available in the literature to represent tissue component material behaviors. Both models are validated against experiments from the literature and used to complete an initial interspecies correspondence rule development study for blast overpressure effects. The results indicate the similarities in the way injury develops in the pig brain and human brain but these similarities occur at very different insult levels. These results are extended by a study, which shows that blast peak pressure is the driving factor in injury prediction and, depending on the injury metric used, significantly different injuries could be predicted.
Assessing the Burden of Chlamydia and Gonorrhea for Deployed and Active Duty Personnel Assigned Outside the USA
Authors: Rossi Kristen R , Nowak Gosia
Published: March 2019

Sexually transmitted infections (STIs) have posed a threat to military service members throughout history, but limited evidence describes current sexually transmitted infection burden for personnel in-theater and stationed abroad. This study assessed chlamydia and gonorrhea rates by unit of country assignment and evaluated the demographic profile of affected personnel during deployment. Chlamydia and gonorrhea cases among active duty personnel were identified from laboratory results and ambulatory encounter records in the Military Health System from fiscal years October 2006 through September 2015; these were linked to personnel and deployment records to ascertain demographic characteristics, unit of country assignment, and if the case was captured during a period of deployment. Case rates were higher for chlamydia (1,321.7 per 100,000) than gonorrhea (222.7 per 100,000). Approximately 2% of both chlamydia and gonorrhea cases were identified during deployment, with significant differences by service, sex, and age. Elevated rates were identified in several countries of unit assignment outside the USA, warranting further assessment to better understand implications of screening programs or increased morbidity. Pertinent limitations for this study potentially underestimate STI cases during deployment, due to incomplete capture of records from shipboard and in-theater facilities.
Differential Effects of Caffeine on Motor and Cognitive Outcomes of Penetrating Ballistic-Like Brain Injury
Authors: Sanjakdar Sarah S , Flerlage William J , Kang Hyun S , Napier Douglas A , Dougherty Jaqueline R , Mountney Andrea , Gilsdorf Janice S , Shear Deborah A
Published: March 2019

This study assessed the effect of caffeine on neurobehavioral recovery in the WRAIR penetrating ballistic-like brain injury (PBBI) model. Unilateral frontal PBBI was produced in the right hemisphere of anesthetized rats at moderate (7%-PBBI) or severe (10%-PBBI) injury levels. Animals were randomly assigned to pretreatment groups: acute caffeine (25 mg/kg CAF gavage, 1 h prior to PBBI), or chronic caffeine (0.25 g/L CAF drinking water, 30 days prior to PBBI). Motor function was evaluated on the rotarod at fixed-speed increments of 10, 15, and 20 RPM. Cognitive performance was evaluated on the Morris water maze. Acute caffeine showed no significant treatment effect on motor or cognitive outcome. Acute caffeine exposure prior to 10%-PBBI resulted in a significantly higher thigmotaxic response compared to vehicle-PBBI groups, which may indicate caffeine exacerbates post-injury anxiety/attention decrements. Results of the chronic caffeine study revealed a significant improvement in motor outcome at 7 and 10 days post-injury in the 7%-PBBI group. However, chronic caffeine exposure significantly increased the latency to locate the platform in the Morris water maze task at all injury levels. Results indicate that chronic caffeine consumption prior to a penetrating TBI may provide moderate beneficial effects to motor recovery, but may worsen the neurocognitive outcome.
Evaluation of the Military Functional Assessment Program for Return-to-Duty Decision Making: A Longitudinal Study
Authors: Kelley Amanda M , Showers Mark
Published: March 2019

Following concussion, return-to-duty decisions are made by medical providers and leaders using informal assessment, review of symptom resolution, and clinical assessments. In an effort to provide military-specific tasks for use in the decision making regarding return-to-duty, a battery developed from the set of basic soldier skills, the Military Functional Assessment Program (MFAP), was evaluated for construct validity using clinical assessment outcomes as well as the relationships between MFAP performance and indicators of long-term performance and satisfaction. A total of 48 participants were enrolled in the study providing baseline and post-treatment clinical assessment, and MFAP performance data. Twenty participants provided follow-up data at 6-month post-MFAP. Correlational analyses suggest significant relationships between MFAP performance ratings and clinical measures of vestibular and cognitive functions and psychological well-being. These findings are consistent with those from previous research on construct validity of the MFAP tasks. Performance on one MFAP task related to perceptions of performance and overall MFAP ratings related to satisfaction reported at 6 months. These findings provide preliminary, however limited, support for these tasks being indicative of the motivation and mental state of the program participant.
Evaluation of Three Postal Invitational Strategies to Increase Survey Response Rates in a Combat-Injured U.S. Military Population: Findings From the Wounded Warrior Recovery Project
Authors: Sack Daniel I , Woodruff Susan I , McCabe Cameron T , Galarneau Michael R , Han Peggy P
Published: March 2019

The survival rate of those injured in combat in overseas contingency operations is higher than in previous conflicts. There is a need to assess the long-term psychosocial and quality of life outcomes of those injured in combat, yet surveying this population presents inherent challenges. As part of a large-scale, longitudinal examination of patient-reported outcomes of service members injured on deployment, the present manuscript evaluated the effectiveness of three postal strategies on response rates: (1) mailing a study prenotification postcard, (2) mailing the survey invitation in a larger envelope, and (3) including a small cash preincentive ($2). Evaluation of these strategies yielded mixed results in this population. Neither the prenotification postcard nor inclusion of a $2 cash preincentive significantly increased response rates. However, use of a larger envelope to mail the survey invitation significantly increased the response rate by 53.1%. Researchers interested in collecting patient-reported outcomes among military populations, including those with combat-related injuries, may find that increasing the visibility of recruitment materials is more effective for improving response rates than attempting to cognitively prime or offer prospective participants preincentives.
Identifying Predictors of Pressurized Submarine Escape Training (PSET) Attrition
Authors: Hughes Linda M , Clarke John
Published: March 2019

Pressurized Submarine Escape Training (PSET) physically prepares submariners to safely escape a submarine at depth. Failure to complete PSET is not a submarine service disqualification. Serious medical incidents are rare, but the safety record tradeoff has been low throughput. From 2009 to 2015, only 34% of students screened completed PSET. Students may be medically screened out of the training altogether (disqualified), or dropout during the physical training (attrite). Training records from 12,122 U.S. Navy students were used to identify factors contributing to training disqualification and attrition. Multivariate logistic regression model predictors included demographic and screening items. Association to PSET disqualification included cold/congestion/cough (ORadj 12.34), limited duty status (ORadj 4.29), Physical Readiness Test failure (ORadj 3.37), pneumonia or bronchitis in last 2 years (ORadj 3.17) and nervousness or anxiety in tight spaces (ORadj 2.37). Basic Enlisted Submarine School students were more likely to be disqualified and attrite than other submariner groups, and black/African American (ORadj 1.53) students were more likely to attrite than white students. Only cold/congestion/cough (ORadj 1.52), trouble swimming (ORadj 1.53), and screening during cold/flu season (ORadj 1.28), were associated with training attrition. Recommendations to modify screening requirements are listed in conclusions.