bluuebunny/crossref_metadata_2025 huggingface dataset:
A screening platform to monitor RNA processing and protein-RNA interactions in ribonuclease P uncovers a small molecule inhibitor
Authors: Madrigal-Carrillo Ezequiel-Alejandro , Díaz-Tufinio Carlos-Alejandro , Santamaría-Suárez Hugo-Aníbal , Arciniega Marcelino , Torres-Larios Alfredo
Published: April 2019

Ribonucleoprotein (RNP) complexes and RNA-processing enzymes are attractive targets for antibiotic development owing to their central roles in microbial physiology. For many of these complexes, comprehensive strategies to identify inhibitors are either lacking or suffer from substantial technical limitations. Here, we describe an activity-binding-structure platform for bacterial ribonuclease P (RNase P), an essential RNP ribozyme involved in 5′ tRNA processing. A novel, real-time fluorescence-based assay was used to monitor RNase P activity and rapidly identify inhibitors using a mini-helix and a pre-tRNA-like bipartite substrate. Using the mini-helix substrate, we screened a library comprising 2560 compounds. Initial hits were then validated using pre-tRNA and the pre-tRNA-like substrate, which ultimately verified four compounds as inhibitors. Biolayer interferometry-based binding assays and molecular dynamics simulations were then used to characterize the interactions between each validated inhibitor and the P protein, P RNA and pre-tRNA. X-ray crystallographic studies subsequently elucidated the structure of the P protein bound to the most promising hit, purpurin, and revealed how this inhibitor adversely affects tRNA 5′ leader binding. This integrated platform affords improved structure-function studies of RNA processing enzymes and facilitates the discovery of novel regulators or inhibitors.
GalaxyRefine2: simultaneous refinement of inaccurate local regions and overall protein structure
Authors: Lee Gyu Rie , Won Jonghun , Heo Lim , Seok Chaok
Published: April 2019

The 3D structure of a protein can be predicted from its amino acid sequence with high accuracy for a large fraction of cases because of the availability of large quantities of experimental data and the advance of computational algorithms. Recently, deep learning methods exploiting the coevolution information obtained by comparing related protein sequences have been successfully used to generate highly accurate model structures even in the absence of template structure information. However, structures predicted based on either template structures or related sequences require further improvement in regions for which information is missing. Refining a predicted protein structure with insufficient information on certain regions is critical because these regions may be connected to functional specificity that is not conserved among related proteins. The GalaxyRefine2 web server, freely available via http://galaxy.seoklab.org/refine2, is an upgraded version of the GalaxyRefine protein structure refinement server and reflects recent developments successfully tested through CASP blind prediction experiments. This method adopts an iterative optimization approach involving various structure move sets to refine both local and global structures. The estimation of local error and hybridization of available homolog structures are also employed for effective conformation search.
Structural basis for the function of SuhB as a transcription factor in ribosomal RNA synthesis
Authors: Huang Yong-Heng , Said Nelly , Loll Bernhard , Wahl Markus C
Published: April 2019

Ribosomal RNA synthesis in Escherichia coli involves a transcription complex, in which RNA polymerase is modified by a signal element on the transcript, Nus factors A, B, E and G, ribosomal protein S4 and inositol mono-phosphatase SuhB. This complex is resistant to ρ-dependent termination and facilitates ribosomal RNA folding, maturation and subunit assembly. The functional contributions of SuhB and their structural bases are presently unclear. We show that SuhB directly binds the RNA signal element and the C-terminal AR2 domain of NusA, and we delineate the atomic basis of the latter interaction by macromolecular crystallography. SuhB recruitment to a ribosomal RNA transcription complex depends on the RNA signal element but not on the NusA AR2 domain. SuhB in turn is required for stable integration of the NusB/E dimer into the complex. In vitro transcription assays revealed that SuhB is crucial for delaying or suppressing ρ-dependent termination, that SuhB also can reduce intrinsic termination, and that SuhB-AR2 contacts contribute to these effects. Together, our results reveal functions of SuhB during ribosomal RNA synthesis and delineate some of the underlying molecular interactions.
Effectiveness of Family Intervention for Preventing Relapse in First-Episode Psychosis Until 24 Months of Follow-up: A Systematic Review With Meta-analysis of Randomized Controlled Trials
Authors: Camacho-Gomez Miguel , Castellvi Pere
Published: April 2019

Background

Relapse risk during the early years of first-episode psychosis (FEP) considerably increases the risk of chronicity. The effectiveness of family intervention for psychosis (FIp) for preventing relapse after FEP remains unknown. We assessed the effectiveness of FIp until 24 months of follow-up for preventing relapse and other relapse-related outcomes in patients following FEP.

Methods

We searched the Cochrane, PubMed, PsycINFO, and ProQuest databases in June 2018. A systematic review with meta-analysis of randomized controlled trials (RCTs), sensitivity analyses, and publication bias were performed, comparing to treatment as usual (TAU) or TAU plus other psychosocial interventions. Outcomes assessed were relapse rates, duration of hospitalization, psychotic symptoms, and functionality. Risk ratios (RRs) and (standardized) mean differences (SMD; MD) were calculated.

Results

Of the 2109 records retrieved, 14 (11 RCTs) were included. Pooled results showed that FIp was effective for preventing relapse (RR = 0.42; 95% CI = 0.29 to 0.61) compared to TAU and/or other psychosocial interventions. It also proved effective when compared to TAU alone (RR = 0.36) and TAU plus other psychosocial interventions (RR = 0.48). FIp showed benefits in reducing duration of hospitalization (TAU, MD = −3.31; other interventions, MD = −4.57) and psychotic symptoms (TAU, SMD = −0.68), and increased functionality (TAU, SMD = 1.36; other interventions, SMD = 1.41).

Conclusions

These findings suggest that FIp is effective for reducing relapse rates, duration of hospitalization, and psychotic symptoms, and for increasing functionality in FEP patients up to 24 months. The study’s main limitations were the inclusion of published research only; authors were not contacted for missing/additional data; and high heterogeneity regarding relapse definition was observed.
Does public outreach impede research performance? Exploring the ‘researcher’s dilemma’ in a sustainability research center
Authors: Kassab Omar
Published: April 2019

Researchers and universities are increasingly urged to communicate their findings to the general public. Despite the broad consensus about the necessity of this task, researchers are still reluctant to engage in public outreach activities. One major reason is that while being somewhat time consuming, engagement in public outreach is not adequately reflected in the metrics that are relevant for career advancement. The study at hand examines to what extent this dilemma is empirically justified. A series of statistical analyses are carried out on the basis of data from a sustainability science research center in Switzerland. The study comes to the conclusion that research performance is overall positively associated to engagement in public outreach activities. This insight has implications for the academic incentive and evaluation system.
Financial Capability and Economic Security among Low-Income Older Asian Immigrants: Lessons from Qualitative Interviews
Authors: Nam Yunju , Sherraden Margaret S , Huang Jin , Lee Eun Jeong , Keovisai Mary
Published: April 2019

This article examines financial capability among low-income older Asian immigrants, using data from in-depth interviews with 13 participants in a subsidized employment program in Los Angeles. Overall, respondents present a portrait of economic insecurity. Qualitative analyses indicate that respondents perceived little need to improve their financial knowledge and management skills because they had “no money to manage.” Most respondents lacked either financial knowledge or financial management skills, which resulted in substantial financial losses among some respondents. Mistrust of financial institutions (“Banks are always vampires”) and other financial barriers (for example, lack of credit history) blocked respondents’ access to formal financial services. In some cases, ethnic financial resources (for example, ethnic banks) reduced the effects of such barriers. There is evidence that respondent financial knowledge and management skills may improve after opening a bank account, suggesting a potential role for financial access in expanding financial capability. Findings demonstrate the importance of financial capability–building interventions for low-income older Asian immigrants. Social workers should be equipped with financial literacy and in-depth understanding of financial needs, perceptions, values, behaviors, and resources of this population.
Biogeographical Network Analysis of Cretaceous Terrestrial Tetrapods: A Phylogeny-Based Approach
Authors: Kubo Tai
Published: April 2019

Network methods are widely used to represent and analyze biogeography. It is difficult, however, to convert occurrence data of fossil vertebrates to a biogeographical network, as most species were known from a single locality. A new method for creating a biogeographical network that can incorporate phylogenetic information is proposed in this study, which increases the number of edges in the network of fossil vertebrates and enables the application of various network methods. Using ancestral state reconstruction via maximum parsimony, the method first estimates the biogeographical regions of all internal nodes of a given phylogeny using biogeographical information on the terminal taxa. Then, each internal node in the phylogenetic tree is converted to an edge in the biogeographical network that connects the region(s), if unambiguously estimated, of its two descendants. The new method was applied to phylogenetic trees generated by a birth–death model. Under all conditions tested, an average of $CDATA[$CDATA[$>$$70% of the internal nodes in phylogenetic trees were converted into edges. Three network indices—link density, average link weight, and endemism index (EI)—were evaluated for their usefulness in comparing different biogeographical networks. The EI reflects the rate of dispersal; the other indices reflect nonbiogeographical parameters, the number of taxa and regions, which highlights the importance of evaluating network indices before applying them to biogeographical studies. Multiple Cretaceous biogeographical networks were constructed from the phylogenies of five tetrapod taxa: terrestrial crocodyliforms, terrestrial turtles, nonavian dinosaurs, avians, and pterosaurs. The networks of avians and pterosaurs showed similar topologies and a strong correlation, and unexpectedly high endemism indices. These similarities were probably a result of shared taphonomic biases (i.e., the Lagerstätten effect) for volant taxa with fragile skeletons. The crocodyliform network was partitioned into the Gondwanan and Laurasian continents. The dinosaur network was partitioned into three groups of continents: 1) North America, Asia, and Australia; 2) Europe and Africa; and 3) India, Madagascar, and South America. When Early and Late Cretaceous dinosaurs were analyzed separately, the dinosaur networks were divided into 1) North America, Asia, and Australia; and 2) Europe, Africa, India, and South America for the Early Cretaceous and 1) North America, Asia, and Europe; and 2) India, Madagascar, and South America for the Late Cretaceous. This partitioning of dinosaur and crocodyliform networks corroborates the results of previous biogeographical studies and indicates that the method introduced here can retrieve biogeographical signals from a source phylogeny when sufficient data are available for most targeted biogeographical regions.
Acetaminophen Responsive miR-19b Modulates SIRT1/Nrf2 Signaling Pathway in Drug-Induced Hepatotoxicity
Authors: Liu Xing , Zhao Hongqian , Luo Chunyan , Du Debin , Huang Jinlong , Ming Quan , Jin Fen , Wang Decheng , Huang Weifeng
Published: April 2019

Previous studies suggest that activation of SIRT1 protects liver from acetaminophen (APAP)-induced injury; however, the detailed mechanism of SIRT1 modulation in this process is still incomplete. Therefore, this study was to investigate the pathophysiological role of SIRT1 in APAP-mediated hepatotoxicity. We found that SIRT1 mRNA and protein were markedly upregulated in human LO2 cells and mouse liver upon APAP exposure. In vitro, the specific knockdown of SIRT1 expression ultimately aggravated APAP-evoked cellular antioxidant defense in LO2 cells. Moreover, lentivirus-mediated knockdown of hepatic SIRT1 expression exacerbated APAP-induced oxidative stress and liver injury, especially reduction of Nrf2 and subsequent downregulation of several antioxidant genes. Intriguingly, 30 mg/kg SRT1720, the specific SIRT1 activator, which greatly enhanced Nrf2 expression and antioxidant defense, and then eventually reversed APAP-induced hepatic liver injury in mice. Furthermore, APAP responsive miR-19b played an important role in regulating SIRT1 expression, whereas overexpression miR-19b largely abolished the induction of SIRT1 by APAP in vitro and in vivo. Specific SIRT1 3′-UTR mutation, which disrupted the interaction of miRNA-3′UTR, and successfully abrogated the modulation by miR-19b. Notably, hepatic miR-19b overexpression worsened the APAP-induced hepatotoxicity. In general, our results support the notion that the strong elevation of SIRT1 by APAP responsive miR-19b may represent a compensatory mechanism to protect liver against the drug-induced damage, at least in part by enhancing Nrf2-mediated antioxidant capacity in the liver.
TSPO PET Using [18F]PBR111 Reveals Persistent Neuroinflammation Following Acute Diisopropylfluorophosphate Intoxication in the Rat
Authors: Hobson Brad A , Rowland Douglas J , Sisó Sílvia , Guignet Michelle A , Harmany Zachary T , Bandara Suren B , Saito Naomi , Harvey Danielle J , Bruun Donald A , Garbow Joel R , Chaudhari Abhijit J , Lein Pamela J
Published: April 2019

Acute intoxication with organophosphates (OPs) can trigger status epilepticus followed by persistent cognitive impairment and/or electroencephalographic abnormalities. Neuroinflammation is widely posited to influence these persistent neurological consequences. However, testing this hypothesis has been challenging, in part because traditional biometrics preclude longitudinal measures of neuroinflammation within the same animal. Therefore, we evaluated the performance of noninvasive positron emission tomography (PET), using the translocator protein (TSPO) radioligand [18F]PBR111 against classic histopathologic measures of neuroinflammation in a preclinical model of acute intoxication with the OP diisopropylfluorophosphate (DFP). Adult male Sprague Dawley rats administered pyridostigmine bromide (0.1 mg/kg, im) 30 min prior to administration of DFP (4 mg/kg, sc), atropine sulfate (2 mg/kg, im) and 2-pralidoxime (25 mg/kg, im) exhibited moderate-to-severe seizure behavior. TSPO PET performed prior to DFP exposure and at 3, 7, 14, 21, and 28 days postexposure revealed distinct lesions, as defined by increased standardized uptake values (SUV). Increased SUV showed high spatial correspondence to immunohistochemical evidence of neuroinflammation, which was corroborated by cytokine gene and protein expression. Regional SUV metrics varied spatiotemporally with days postexposure and correlated with the degree of neuroinflammation detected immunohistochemically. Furthermore, SUV metrics were highly correlated with seizure severity, suggesting that early termination of OP-induced seizures may be critical for attenuating subsequent neuroinflammatory responses. Normalization of SUV values to a cerebellar reference region improved correlations to all outcome measures and seizure severity. Collectively, these results establish TSPO PET using [18F]PBR111 as a robust, noninvasive tool for longitudinal monitoring of neuroinflammation following acute OP intoxication.
The Relationship of Employment Scarcity and Perceived Threat With Ageist and Sexist Attitudes
Authors: Ospina Javier H , Cleveland Jeanette N , Gibbons Alyssa M
Published: April 2019

Using theories of intergroup relations, the current research examined whether personal experiences and perceptions of employment hardship (e.g., unemployment, underemployment, perceived job insecurity, and career optimism) were associated with ageist and sexist attitudes among younger workers and male workers toward older workers and female workers, respectively. In Study 1, a survey of working adults found that, among those under 35, underemployment and job insecurity predicted perceived threat from older workers, which was associated with ageist attitudes. In Study 2, in a survey of college students under age 35, career optimism was associated with the perceived threat from older workers, which was correlated with ageist attitudes. Among men, perceived job insecurity predicted threat from women, which was associated with sexist attitudes. These results suggest that groups traditionally viewed as noncompetitive or nonthreatening may be viewed more negatively (in ageist or sexist terms) under conditions of individual-level actual and perceived resource scarcity and competition.
Characterization of the Race Structure of Leptosphaeria maculans Causing Blackleg of Winter Canola in Oklahoma and Kansas
Authors: Diaz Claudia , Cevallos Felipe , Damicone John
Published: April 2019

Blackleg, caused by the fungus Leptosphaeria maculans, is a widespread disease of winter canola (Brassica napus) in Oklahoma and Kansas. Deployment of genetic resistance is the primary strategy for managing blackleg. Resistance genes (Rlm) in canola interact with avirulence genes in the fungus (AvrLm) in a gene-for-gene manner. Little is known about the diversity and frequency of avirulence genes and the race structure in the region. Isolates of Leptosphaeria spp. were collected from diseased leaves in nine counties in Oklahoma and one county in Kansas from 2009 to 2013. Based on pathogenicity and PCR amplification of mating type and species-specific internal transcribed spacer loci, most isolates (n = 90) were L. maculans. The presence of avirulence genes was evaluated using phenotypic interactions on cotyledons of differential cultivars with Rlm1, Rlm2, Rlm3, and Rlm4 and amplification of AvrLm1, AvrLm4-7, and AvrLm6 by PCR. The avirulence alleles AvrLm6 and AvrLm7 were present in the entire L. maculans population. AvrLm1 was found in 34% of the population, AvrLm2 in 4%, and AvrLm4 in only 1%. A total of five races, defined as combinations of avirulence alleles, were identified that included AvrLm1-2-6-7, AvrLm2-6-7, AvrLm4-6-7, AvrLm1-6-7, and AvrLm6-7. Races virulent on the most Rlm genes, AvrLm1-6-7 at 32% and AvrLm6-7 at 62%, were predominant. Defining the avirulence allele frequency and race structure of L. maculans should be useful for the identification and development of resistant cultivars and hybrids for blackleg management in the region. The results suggest that Rlm6 and Rlm7 would be effective, although their deployment should be integrated with quantitative resistance and cultural practices, such as crop rotation, that limit selection pressure on Rlm genes.
Understanding the Process of Latent Infection of Canker-Causing Pathogens in Stone Fruit and Nut Crops in California
Authors: Luo Yong , Lichtemberg Paulo S. F. , Niederholzer Franz J. A. , Lightle Danielle M. , Felts Daniel G. , Michailides Themis J.
Published: April 2019

The Botryosphaeriaceae family is considered a fungal family that includes pathogens causing latent infection of woody plants, and a number of species were identified as causal pathogens of canker and shoot blight diseases. To better understand the process of latent infection of major canker-causing pathogens in woody tissues in different tree crops important in California, shoot and bud samples were randomly collected from four tree crops: almond, dried plum, pistachio, and walnut. The previously developed DNA primers and quantitative real-time PCR (qPCR) assay systems were applied to detect six canker-causing pathogen groups, including Botryosphaeria dothidea, and species of Cytospora, Diplodia, Lasiodiplodia, Neofusicoccum, and Phomopsis. The concepts of molecular severity (MS) and latent infection index (LII) were introduced and applied to quantify the latent infection levels for these samples. Variation in incidence of latent infection among pathogen groups was observed, whereas the incidences were relatively low among species of Phomopsis and Diplodia. High incidences of Cytospora spp. were observed in two dried plum (prune) orchards. Most orchards showed high incidences of B. dothidea and Lasiodiplodia spp. and moderate incidences of Neofusicoccum spp. Variations in MS were observed among samples of the studied orchards, ranging from 4 to 8. The overall results of LII demonstrated that species of Diplodia and Phomopsis were less important in population development of canker-causing pathogens at the latent phase. Lasiodiplodia spp. were the most aggressive and had been well developed in populations among the studied tree crops. Cytospora spp. became predominant in two of the three dried plum orchards, whereas B. dothidea and Neofusicoccum spp. showed trends of increase in incidence across various tree crops. This study also demonstrated the usefulness of this sensitive qPCR approach in providing evidence of the latent phase of major canker-causing pathogens of stone fruit and nut crops at an early stage of latent infection in woody plant tissues.
A Core Components Framework for Evaluating Implementation of Competency-Based Medical Education Programs
Authors: Van Melle Elaine , Frank Jason R. , Holmboe Eric S. , Dagnone Damon , Stockley Denise , Sherbino Jonathan
Published: April 2019

Purpose

The rapid adoption of competency-based medical education (CBME) provides an unprecedented opportunity to study implementation. Examining “fidelity of implementation”—that is, whether CBME is being implemented as intended—is hampered, however, by the lack of a common framework. This article details the development of such a framework.

Method

A two-step method was used. First, a perspective indicating how CBME is intended to bring about change was described. Accordingly, core components were identified. Drawing from the literature, the core components were organized into a draft framework. Using a modified Delphi approach, the second step examined consensus amongst an international group of experts in CBME.

Results

Two different viewpoints describing how a CBME program can bring about change were found: production and reform. Because the reform model was most consistent with the characterization of CBME as a transformative innovation, this perspective was used to create a draft framework. Following the Delphi process, five core components of CBME curricula were identified: outcome competencies, sequenced progression, tailored learning experiences, competency-focused instruction, and programmatic assessment. With some modification in wording, consensus emerged amongst the panel of international experts.

Conclusions

Typically, implementation evaluation relies on the creation of a specific checklist of practices. Given the ongoing evolution and complexity of CBME, this work, however, focused on identifying core components. Consistent with recent developments in program evaluation, where implementation is described as a developmental trajectory toward fidelity, identifying core components is presented as a fundamental first step toward gaining a more sophisticated understanding of implementation.
Importance of Syndesmotic Reduction on Clinical Outcome After Syndesmosis Injuries
Authors: Andersen Mette R. , Diep Lien M. , Frihagen Frede , Castberg Hellund Johan , Madsen Jan E. , Figved Wender
Published: April 2019

Objectives:

To evaluate the relationship between syndesmosis reduction and outcome.

Design:

Retrospective cohort study.

Setting:

One Level 1 and 1 Level 3 Trauma Center.

Patients:

Ninety-seven patients with syndesmosis injury.

Intervention:

Stabilization of syndesmosis injury. Open reduction and internal fixation of malleolar fracture, if present.

Main Outcome Measurements:

Anterior, central, and posterior measures of syndesmosis width on computed tomography scans, Olerud–Molander Ankle score, American Orthopaedic Foot and American Orthopaedic Foot and Ankle Society Ankle-Hindfoot score, and range of motion measurements.

Results:

Eighty-seven patients completed 2 years of follow-up. The difference in anterior tibiofibular distance (aTFD) between the injured and noninjured ankle postoperatively had a significant effect on the Olerud-Molander Ankle score after 6 weeks [b = −2.6, 95% confidence interval (CI), −4.8 to −0.4; P = 0.02], 1 year (b = −2.7, 95% CI, −4.7 to −0.8; P < 0.001), and 2 years (b = −2.6, 95% CI, −4.6 to −0.6; P = 0.009) and on American Orthopaedic Foot and Ankle Society Ankle-Hindfoot score after 6 weeks (b = −2.2, 95% CI, −3.7 to −0.7; P = 0.004), 1 year (b = −1.7, 95% CI, −3.0 to −0.4; P = 0.04), and 2 years (b = −1.9, 95% CI, −3.2 to −0.5; P = 0.006). The effect of computed tomography measurements on range of motion was inconsistent. Receiver operating characteristic (ROC) curves demonstrated that aTFD had adequate discriminatory performance (area under the ROC curve ≥ 0.7) 1 and 2 years after surgery and the central measurement at only 2 years after surgery. ROC analyses indicate a cutoff value for syndesmosis malreduction of 2 mm. The postoperative rate of malreduction was 32%.

Conclusions:

The aTFD correlated with clinical outcome. A 2-mm difference in aTFD seems to predict poorer clinical outcome.

Level of Evidence:

Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Radiographic Evaluation of Bone Remodeling Around Osseointegration Implants Among Transfemoral Amputees
Authors: Thomson Seamus , Thomson Alasdair , Tetsworth Kevin , Lu William , Zreiqat Hala , Al Muderis Munjed
Published: April 2019

Objectives:

To examine periprosthetic bone remodeling among the recipients of 2 types of lower-limb osseointegrated systems, the Integral Leg Prosthesis (ILP) and the Osseointegration Prosthetic Limb (OPL) type A, over a >24-month period.

Design:

Retrospective cohort study.

Setting:

Private hospital, with a specialized osseointegration unit.

Patients:

Twenty-eight patients with transfemoral lower-limb amputations were fitted with osseointegrated systems. Of these patients, 15 received the ILP and 13 the OPL osseointegrated implant.

Intervention:

Radiographic measurements were taken at baseline (0.4 ± 0.5 years) and at follow-up (3.0 ± 0.8 years) after the osseointegration procedure.

Main Outcome Measurements:

Radiographic bone density, longitudinal bone coverage, and bone width outcomes were measured in inverse “Gruen zones.” Bone remodeling was evaluated by comparing changes between baseline and follow-up measurements.

Results:

Radiographic bone density decreased in all zones among both ILP and OPL groups. Cortical bone thickness increased among the OPL group in zones 3 (P < 0.05) and 5 (P < 0.05). Distal bone coverage of the ILP implant decreased by 2.3% (P < 0.01) and 4.1% (P < 0.05) of the total implant length on the medial and lateral sides, respectively.

Conclusions:

Decreased bone density with increased periprosthetic cortical thickness suggests a change in the bone architecture for the OPL group. The findings of this study raise concerns for the long-term success of the ILP implant. Radiographic analysis of x-rays seems to be a useful tool for clinicians to evaluate bone remodeling around osseointegrated prosthesis.

Level of Evidence:

Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
The Role of Type I Diabetes in Intervertebral Disc Degeneration
Authors: Russo Fabrizio , Ambrosio Luca , Ngo Kevin , Vadalà Gianluca , Denaro Vincenzo , Fan Yong , Sowa Gwendolyn , Kang James D. , Vo Nam
Published: April 2019

Study Design.

An experimental laboratory study.

Objective.

To investigate the pathogenesis of intervertebral disc degeneration (IDD) in a murine model of type 1 diabetes mellitus (DM), namely nonobese diabetic (NOD) mouse.

Summary of Background Data.

IDD is a leading contributor of low back pain, which represents one of the most disabling symptoms within the adult population. DM is a chronic metabolic disease currently affecting one in 10 adults in the United States. It is associated with an increased risk of developing IDD, but the underlying process remains poorly understood.

Methods.

Total disc glycosaminoglycan content, proteoglycan synthesis, aggrecan fragmentation, glucose transporter gene expression, and apoptosis were assessed in NOD mice and wild-type euglycemic control mice. Spinal structural and molecular changes were analyzed by micro-computed tomography, histological staining (Safranin-O and fast green), and quantitative immunofluorescence (anti-ADAMTS-4 and -5 antibodies).

Results.

Compared with euglycemic controls, NOD mice showed increased disc apoptosis and matrix aggrecan fragmentation. Disc glycosaminoglycan content and histological features of NOD mice did not significantly differ from those of euglycemic littermates.

Conclusion.

These data demonstrate that DM may contribute to IDD by increasing aggrecan degradation and promoting cell apoptosis, which may represent early indicators of the involvement of DM in the pathogenesis of IDD.

Level of Evidence: N/A
Sex Differences in Rat Intervertebral Disc Structure and Function Following Annular Puncture Injury
Authors: Mosley Grace E. , Hoy Robert C. , Nasser Philip , Kaseta Timothy , Lai Alon , Evashwick-Rogler Thomas W. , Lee Michael , Iatridis James C.
Published: April 2019

Study Design.

A rat puncture injury intervertebral disc (IVD) degeneration model with structural, biomechanical, and histological analyses.

Objective.

To determine if males and females have distinct responses in the IVD after injury.

Summary of Background Data.

Low back pain (LBP) and spinal impairments are more common in women than men. However, sex differences in IVD response to injury have been underexplored, particularly in animal models where sex differences can be measured without gender confounds.

Methods.

Forty-eight male and female Sprague Dawley rats underwent sham, single annular puncture with tumor necrosis factor α (TNFα) injection (1×), or triple annular puncture with TNFα injection (3×) surgery. Six weeks after surgery, lumbar IVDs were assessed by radiologic IVD height, spinal motion segment biomechanical testing, histological degeneration grading, second harmonic generation (SHG) imaging, and immunofluorescence for fibronectin and α-smooth muscle actin.

Results.

Annular puncture injuries significantly increased degenerative grade and IVD height loss for males and females, but females had increased degeneration grade particularly in the annulus fibrosus (AF). Despite IVD height loss, biomechanical properties were largely unaffected by injury at 6 weeks. However, biomechanical measures sensitive to outer AF differed by sex after 3× injury—male IVDs had greater torsional stiffness, torque range, and viscoelastic creep responses. SHG intensity of outer AF was reduced after injury only in female IVDs, suggesting sex differences in collagen remodeling. Both males and females exhibited decreased cellularity and increased fibronectin expression at injury sites.

Conclusion.

IVD injury results in distinct degeneration and functional healing responses between males and females. The subtle sex differences identified in this animal model suggest differences in response to IVD injury that might explain some of the variance observed in human LBP, and demonstrate the need to better understand differences in male and female IVD degeneration patterns and pain pathogenesis.

Level of Evidence: N/A
Short-term Outcomes Following Cervical Laminoplasty and Decompression and Fusion With Instrumentation
Authors: Boniello Anthony , Petrucelli Philip , Kerbel Yudi , Horn Samantha , Bortz Cole A. , Brown Avery E. , Pierce Katherine E. , Alas Haddy , Khalsa Amrit , Passias Peter
Published: April 2019

Study Design.

Retrospective review of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database years 2010 to 2015.

Objective.

Investigate which short-term outcomes differ for cervical laminoplasty and laminectomy and fusion surgeries.

Summary of Background Data.

Conflicting reports exist in spine literature regarding short-term outcomes following cervical laminoplasty and posterior laminectomy and fusion. The objective of this study was to compare the 30-day outcomes for these two treatment groups for multilevel cervical pathology.

Methods.

Patients who underwent cervical laminoplasty or posterior laminectomy and fusion were identified in National Surgical Quality Improvement Program (NSQIP) based on Current Procedural Terminology (CPT) code: laminoplasty 63,050 and 63,051, posterior cervical laminectomy 63,015 and 63,045, and instrumentation 22,842. Propensity-adjusted multivariate regressions assessed differences in postoperative length of stay, adverse events, discharge disposition, and readmission.

Results.

Three thousand seven hundred ninety-six patients were included: 2397 (63%) underwent cervical laminectomy and fusion and 1399 (37%) underwent cervical laminoplasty. Both groups were similar in age, sex, body mass index (BMI), American Society of Anesthesiologist Classification (ASA), Charleston Comorbidity Index (CCI), and had similar rates of malnutrition, chronic kidney disease, diabetes, chronic obstructive pulmonary disease, and history for steroid use. Age more than 70 and age less than 50 were not associated with one treatment group over the other (P > 0.05). Compared with laminoplasty patients, laminectomy and fusion patients had increased lengths of stay (LOS) (4.5 vs. 3.7 d, P < 0.01) and increased rates of adverse events (41.7% vs. 35.9%, P < 0.01), discharge to rehab (16.4% vs. 8.6%, P < 0.01), and skilled nursing facilities (12.2% vs. 9.7%, P = 0.02), and readmission (6.2% vs. 4.5%, P = 0.05). Both groups experienced similar rates of death, pulmonary embolus, deep vein thrombosis, deep and superficial surgical site infection, and reoperation (P > 0.05 for all).

Conclusion.

Posterior cervical laminectomy and fusion patients were found to have increased LOS, readmissions, and complications despite having similar pre-op demographics and comorbidities. Patients and surgeons should consider these risks when considering surgical treatment for cervical pathology.

Level of Evidence: 3
Techniques for Continuous Irrigation of Septic Joints of the Hand
Authors: Chung Sze-Ryn , Kang Yong Chiang , McGrouther Duncan Angus
Published: April 2019

Septic arthritis of the small joints of the hand usually occurs secondary to bacterial inoculation through penetrating injury to the joint, or direct spread of infection from paronychia, felon, or pyogenic flexor tenosynovitis. Surgical treatment involves drainage and irrigation and may involve debridement if there is an open wound. We describe a method of continuous irrigation of septic joints of the hand postoperatively in the ward setting using an intravenous cannula placed within the joint and connected to an intravenous giving set with delivery of physiological fluid using a pump driver. Modifications of the technique are described for distal interphalangeal, proximal interphalangeal, and metacarpophalangeal joints and illustrated in each joint by 3 case studies. In addition to the irrigation, intravenous antibiotics were administered. All patients healed well with a full return of joint motion, no radiologic change, and a mean QuickDASH score of 4.8 at a mean follow-up duration of 3.6 months. This is a safe and simple technique that can be performed in patients with suspected or confirmed septic arthritis and carries minimal morbidity.
Conditional Survival Analysis of Metastatic Colorectal Cancer Patients Living ≥24 Months
Authors: Ali Nadia D. , Donohue Kristen , Zandieh Shadi , Chen Chunxia , Moore Dirk , Poplin Elizabeth , Shah Mihir M. , Nosher John , Gui Bin , Jabbour Salma K. , Spencer Kristen , Carpizo Darren R.
Published: April 2019

Objectives:

The survival of patients with metastatic colorectal cancer (CRC) has been increasing over recent decades due to improvements in chemotherapy and surgery. There is a need to refine prognostic information to more accurately predict survival as patients survive for any given length of time to assist multidisciplinary cancer management teams in treatment decisions.

Materials and Methods:

We performed a single center retrospective analysis of patients treated with metastatic CRC (unresectable and resectable) who survived >24 months between 2005 and 2015 (N=155). Patient tumor and treatment related variables were collected. Overall survival (OS) estimates conditional on surviving >24 months were compared with actuarial survival estimates of a cohort of patients (33,104 resected, 39,382 unresected) from the National Cancer Database (NCDB).

Results:

With a median follow-up of 44.2 months, the median OS of resected patients (n=86) was not reached. The median OS of unresected patients was 75.9 months. The conditional survival probabilities of living 1, 2, or 3 years longer after 24 months of survival are 92%, 72%, and 52%, respectively, in unresectable patients and 98%, 92%, and 89% in patients who were resected. The corresponding NCDB 1, 2, and 3 year actuarial survival was 38%, 20%, and 11% for unresected patients and 68%, 46%, and 32% for resected.

Conclusions:

These results indicate that CRC patients who survive 24 months with metastatic colorectal cancer have an excellent prognosis and surgery may be appropriate in a subset of patients initially deemed unresectable.
Efficacy and Safety of Gefitinib as Third-line Treatment in NSCLC Patients With Activating EGFR Mutations Treated With First-line Gefitinib Followed by Second-line Chemotherapy
Authors: Song Yong , Wu Yi-Long , Cao Le-Jie , Chen Jian-Hua , Ma Zhi-Yong , Cui Jiu-Wei , Wang Jie , Liu Hong-Bing , Ding Jing-Yan , Hu Min
Published: April 2019

Objective:

There is no standard care for advanced non–small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation in the third line. Our study aimed to assess the efficacy and safety of gefitinib as a third-line re-challenge treatment for advanced NSCLC patients with EGFR mutation.

Materials and Methods:

It was a multicenter, open-label, single-arm, phase II study. Stage IIIB/IV NSCLC patients with EGFR exon 19del/L858R mutation, who had benefited from first-line gefitinib treatment followed by second-line chemotherapy, received gefitinib 250 mg/d. The primary objective was disease control rate (DCR) at week 8.

Results:

Predefined DCR was achieved in 69.8% (95% confidence interval, 49.87-74.91) patients and objective response rate was reported in 4.7% (95% confidence interval, 0.78-13.06) patients. Median progression-free survival (PFS) was 4.4 months and overall survival (OS) was 10.3 months. Baseline T790M-negative patients achieved favorable DCR compared with T790M-positive patients (78.1% vs. 45.5%, P=0.0418), significantly longer median PFS (4.7 vs. 2.0 mo, P=0.0009) and median OS (15.2 vs. 7.7 mo, P=0.0132). We observed a negative correlation of PFS (r=−0.4396, P=0.0032), and OS (r=−0.3630, P=0.0167) with mutation abundance of exon 19del/L858R at baseline.

Conclusions:

Re-challenge with gefitinib is effective and could be a choice for third-line patients after the first-line EGFR-TKI treatment and second-line chemotherapy, especially for the T790M-negative patients.
Uterine Papillary Serous Carcinoma Arising in a Polyp
Authors: Mandato Vincenzo D. , Torricelli Federica , Palomba Stefano , Uccella Stefano , Pirillo Debora , Ciarlini Gino , De Iaco Pierandrea , Lucia Emilio , Giorda Giorgio , Ditto Antonino , Ghezzi Fabio , Sanseverino Francesca , Franchi Massimo , Bifulco Giuseppe , Mastrofilippo Valentina , Abrate Martino , Aguzzoli Lorenzo , La Sala Giovanni B.
Published: April 2019

Objectives:

The objectives of this study were to evaluate whether the international recommendations on the management of uterine papillary serous carcinoma arising in a polyp are uniformly followed in Italian Oncologic Centers and whether the strategy adopted is effective.

Materials and Methods:

Patients with uterine papillary serous carcinoma arising in a polyp and who had undergone a hysterectomy were identified in the 2003-2013 database of 7 Italian Gynecologic Oncology Centers. Clinical and pathologic characteristics and outcomes were compared between staging procedure types. Survival curves of the women were plotted using the Kaplan-Meier method and analyzed using Cox regression hazard model and the log-rank test. Associations between clinical parameters and the incidence of recurrence were assessed by generalized linear models and the Fisher test.

Results:

A total of 75 patients met the inclusion criteria. Recurrence-free survival was affected positively by type of surgical staging and negatively by preoperative diagnosis of hypertension. The association between surgical staging and recurrence-free survival resulted significant at univariate survival analysis (P=0.048 and 0.045) and maintained a trend of significance (P=0.070) in multivariate analysis, whereas hypertension was demonstrated to be the principal influencing factor.

Conclusions:

The international recommendations on the management of uterine papillary serous carcinoma are not uniformly followed in daily practice, although the extension of the surgery seems to be associated with lower recurrence rates also when uterine papillary serous carcinoma is confined to a polyp or endometrial surface.
Analysis of Outcomes in Patients With BRCA1/2 Breast Cancer Mutations Treated With Accelerated Partial Breast Irradiation (APBI)
Authors: Ahmed Faisal , Christos Paul J. , Singh Prabhsimranjot , Parashar Bhupesh , Wernicke Alla Gabriella
Published: April 2019

Objective:

To analyze outcomes and survival for BRCA1/2+ patients treated with accelerated partial breast irradiation (APBI).

Materials and Methods:

Retrospective review was performed on 341 women treated with intracavitary APBI (Mammosite or Contura) postlumpectomy from 2002 to 2013. Patients were treated to 34.0 Gy in 10 BID fractions. Of 341 treated patients, 11 (3.2%) had BRCA1/2 mutations, 5 of whom had an oophorectomy. Ipsilateral breast tumor recurrence (IBTR), contralateral breast tumor recurrence (CBTR), and breast tumor recurrence progression-free survival were analyzed using SPSS-17. BRCA1/2+ patient outcomes were compared with a general population treated cohort.

Results:

Median age at diagnosis was 66 years, for BRCA1/2+ women it was 61 years. Median follow-up was 8.4 years and for BRCA1/2+ patients it was 8.8 years. IBTR for the entire cohort was 3.5%, while CBTR was 1.2%. Both IBTR and CBTR for the BRCA1/2+ group were 0%. The 5-year IBTR-free survival was 97.3% (95% confidence interval [CI]=94.9%, 98.6%), and the CBTR-free survival was 99.4% (95% CI=97.6%, 99.9%). The 5-year breast tumor recurrence-free survival was 96.7% (95% CI=94.1%, 98.2%). As no patients with BRCA1/2+ mutation died of metastatic breast cancer or recurrence during follow-up and review, overall survival could not be evaluated.

Conclusions:

To date, BRCA1/2+ patients treated with APBI sustained no recurrences, or second cancers. Most patients had an ER+ status and underwent oophorectomy, which may be a protective mechanism for recurrence. This is the first outcomes report in the literature of BRCA1/2 mutations treated with APBI technique.
Phase I Study of Aurora A Kinase Inhibitor Alisertib (MLN8237) in Combination With Selective VEGFR Inhibitor Pazopanib for Therapy of Advanced Solid Tumors
Authors: Shah Hiral A. , Fischer James H. , Venepalli Neeta K. , Danciu Oana C. , Christian Sonia , Russell Meredith J. , Liu Li C. , Zacny James P. , Dudek Arkadiusz Z.
Published: April 2019

Objectives:

Pazopanib is a multikinase angiogenesis inhibitor. Alisertib is a highly selective inhibitor of mitotic Aurora A kinase. There is preclinical evidence that mitosis-targeting agents exhibit antiangiogenic effects. Thus, the combination of these 2 agents may have a synergistic effect on tumor vasculature. The primary objective of this study is to determine the optimal tolerated dose (OTD) for alisertib and pazopanib.

Materials and Methods:

This phase 1b study evaluated the OTD of alisertib twice a day, on days 1 to 7 with pazopanib, once a day, continuously in a 21-day cycle, both taken orally. Disease response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 every 2 cycles. OTD cohort was expanded to assure safety and perform pharmacokinetics analysis.

Results:

A total of 27 patients received treatment. Seventy-seven percent of the patients had received at least 3 prior chemotherapy regimens. Dose-limiting toxicities occurred in dose level (DL) 2+ (grade 4 thrombocytopenia and grade 3 mucositis) and DL 3 (grade 3 liver transaminases elevation and grade 3 abdominal pain). The OTD was determined to be DL 2: alisertib 20 mg twice daily and pazopanib 600 mg daily. Pharmacokinetic analysis revealed that clearance of alisertib was reduced by ∼40% in the presence of pazopanib compared with clearance in the absence of pazopanib. Fourteen patients had stable disease and 2 patients had a partial response.

Conclusions:

The combination of alisertib with pazopanib demonstrates manageable safety and early clinical evidence of antitumor activity in patients with advanced malignancies (NCT01639911).
Digital Media and Autism Spectrum Disorders: Review of Evidence, Theoretical Concerns, and Opportunities for Intervention
Authors: Lane Rebecca , Radesky Jenny
Published: April 2019

As the digital media landscape becomes more complex, individualized, and interactive, pediatric providers often find themselves asked to be the source of guidance for children with developmental and behavioral conditions such as autism spectrum disorder (ASD). In this brief report, we review the current literature that exists regarding the use of traditional media (e.g., TV, video games) in children with ASD. We then outline a conceptual framework to describe the interaction between ASD-specific developmental and behavioral vulnerabilities and the aspects of new media (e.g., mobile devices, interactive apps, streaming video services) that could lead to problematic media use. This conceptual framework is then applied to clinical implications for how to prevent and manage problematic media usage in ASD and how to use modern media as tools to support optimal development.
Patient-reported outcome measures in benign gynecologic surgery: updates and selected tools
Authors: Traylor Jessica , Chaudhari Angela , Tsai Susan , Milad Magdy P.
Published: April 2019

Purpose of review

Use of patient-reported outcome measures in clinical practice and research is becoming more prevalent and reflects initiatives to center the patient in healthcare delivery and outcomes assessment. The purpose of this review is to provide a summary description of selected, validated tools used to assess outcomes related to several benign gynecologic conditions: abnormal uterine bleeding, fibroids and endometriosis.

Recent findings

Given the availability of several validated instruments to assess patient outcomes in benign gynecology, there is still significant heterogeneity in tools used in trials.

Patient outcomes assessment should be an integral part of clinical practice and research in order to treat the whole patient and address any health-related impacts on quality of life. More attention is needed to increase standardization of tools used in research to facilitate assessment of comparative efficacy between treatments.