bluuebunny/crossref_metadata_2025 huggingface dataset:
Linking Mitochondrial Dysfunction to Organismal and Population Health in the Context of Environmental Pollutants: Progress and Considerations for Mitochondrial Adverse Outcome Pathways
Authors: Dreier David A. , Mello Danielle F. , Meyer Joel N. , Martyniuk Christopher J.
Published: May 2019

Mitochondria are key targets of many environmental contaminants, because specific chemicals can interact directly with mitochondrial proteins, lipids, and ribonucleic acids. These direct interactions serve as molecular initiating events that impede adenosine triphosphate production and other critical functions that mitochondria serve within the cell (e.g., calcium and metal homeostasis, apoptosis, immune signaling, redox balance). A limited but growing number of adverse outcome pathways (AOPs) have been proposed to associate mitochondrial dysfunction with effects at organismal and population levels. These pathways involve key events such as altered membrane potential, mitochondrial fission/fusion, and mitochondrial DNA damage, among others. The present critical review and analysis reveals current progress on AOPs involving mitochondrial dysfunction, and, using a network-based computational approach, identifies the localization of mitochondrial molecular initiating events and key events within multiple existing AOPs. We also present 2 case studies, the first examining the interaction between mitochondria and immunotoxicity, and the second examining the role of early mitochondrial dysfunction in the context of behavior (i.e., locomotor activity). We discuss limitations in our current understanding of mitochondrial AOPs and highlight opportunities for clarifying their details. Advancing our knowledge of key event relationships within the AOP framework will require high-throughput datasets that permit the development and testing of chemical-agnostic AOPs, as well as high-resolution research that will enhance the mechanistic testing and validation of these key event relationships. Given the wide range of chemicals that affect mitochondria, and the centrality of energy production and signaling to ecologically important outcomes such as pathogen defense, homeostasis, growth, and reproduction, a better understanding of mitochondrial AOPs is expected to play a significant, if not central, role in environmental toxicology. Environ Toxicol Chem 2019;38:1625–1634. © 2019 SETAC
A novel dynamic framework to detect DDoS in SDN using metaheuristic clustering
Authors: Shakil Muhammad , Fuad Yousif Mohammed Alaelddin , Arul Rajakumar , Bashir Ali Kashif , Choi Jun Kyun
Published: May 2019

Security is a crucial factor in the continuously evolving programmable networks. With the emergence of programmable networking terminals, the need to protect the networks has become mandatory. Software‐defined networks (SDNs) provide programmable switches, thereby isolating the data plane from the control plane. Many security algorithms have been proposed to protect the network; however, they have failed to protect SDNs from attacks such as distributed denial of service (DDoS), jamming, and man‐in‐the‐middle attacks. In this article, we only address the DDoS attack that prevails in SDNs. Isolation of the control plane from the data plane increases the probability of an attack on the data plane. Therefore, a framework that can handle the dynamic traffic and can protect the network from DDoS attacks is required. Our proposed whale optimization algorithm–based clustering for DDoS detection (WOA‐DD) avoids the DDoS attacks using a metaheuristic approach by clustering the attack requests. We evaluated this algorithm for robustness in comparison with several existing solutions and found it to be safe under several conditions. The proposed attack request clustering is explored to check its feasibility with various machine learning approaches and found to be stable with the prevailing mechanisms. Analysis of the algorithm under varied conditions reveals that WOA‐DD is robust, stable, and efficient against DDoS attacks.
Aging restricts the ability of mesenchymal stem cells to promote the generation of oligodendrocytes during remyelination
Authors: Rivera Francisco J. , de la Fuente Alerie G. , Zhao Chao , Silva Maria E. , Gonzalez Ginez A. , Wodnar Roman , Feichtner Martina , Lange Simona , Errea Oihana , Priglinger Eleni , O'Sullivan Anna , Romanelli Pasquale , Jadasz Janusz J. , Brachtl Gabriele , Greil Richard , Tempfer Herbert , Traweger Andreas , Bátiz Luis F. , Küry Patrick , Couillard‐Despres Sebastien , Franklin Robin J. M. , Aigner Ludwig
Published: May 2019

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that leads to severe neurological deficits. Due to their immunomodulatory and neuroprotective activities and their ability to promote the generation of oligodendrocytes, mesenchymal stem cells (MSCs) are currently being developed for autologous cell therapy in MS. As aging reduces the regenerative capacity of all tissues, it is of relevance to investigate whether MSCs retain their pro‐oligodendrogenic activity with increasing age. We demonstrate that MSCs derived from aged rats have a reduced capacity to induce oligodendrocyte differentiation of adult CNS stem/progenitor cells. Aging also abolished the ability of MSCs to enhance the generation of myelin‐like sheaths in demyelinated cerebellar slice cultures. Finally, in a rat model for CNS demyelination, aging suppressed the capability of systemically transplanted MSCs to boost oligodendrocyte progenitor cell (OPC) differentiation during remyelination. Thus, aging restricts the ability of MSCs to support the generation of oligodendrocytes and consequently inhibits their capacity to enhance the generation of myelin‐like sheaths. These findings may impact on the design of therapies using autologous MSCs in older MS patients.
Dementia outcomes after addition of proxy‐based assessments for deceased or proxy‐dependent participants
Authors: Gaussoin Sarah A. , Espeland Mark A. , Beavers Daniel P. , Casanova Ramon , Garcia Katelyn R. , Snively Beverly M. , Shumaker Sally A. , Wallace Robert B. , Rapp Stephen R.
Published: May 2019

Objectives

As people age and the incidence of dementia increases, studies of cognitive function continue to be of importance. Ascertaining cognitive data through different mechanisms is necessary to address missing data concerns.

Methods

The Dementia Questionnaire (DQ), which utilizes proxy‐based assessments, is a potential tool to determine cognitive status in participants no longer being followed per traditional study protocol. The DQ is currently being used in the Supplemental Case Ascertainment Protocol (SCAP), which is being conducted in an ongoing study of postmenopausal women as part of the Women's Health Initiative Memory Study (WHIMS).

Results

Ninety‐four percent of the 1260 SCAP participants were eligible because of being deceased. Those who are SCAP eligible were older, were less likely to be a minority, and were more likely to have hypertension, diabetes, and prior history of cardiovascular disease (CVD) as well as being a past or current smoker. SCAP added 109 cases of probable dementia to WHIMS. Risk factor relationships were modified upon inclusion of the SCAP cases including an attenuation of a hormone therapy effect and discovery of a hypertension effect.

Conclusions

Augmenting clinic‐based cases with proxy‐based assessments is feasible and leads to increased incident cases of dementia. When planning future clinical trials, it may be of study benefit to include a protocol of proxy‐based assessments, develop strong relationships with proxies early on in the study, and attempt to maintain this relationship throughout the lifespan of the trial.
The impact of military service on the mental health of older UK veterans: A qualitative study
Authors: Williamson Victoria , Harwood Hannah , Greenberg Karla , Stevelink Sharon A.M. , Greenberg Neil
Published: May 2019

Background

There may be ongoing psychological problems associated with military service later in life; yet as the elderly in the general population also suffer from mental health problems, whether such issues can be attributed to military service or are a feature of ageing remains unclear. This study aimed to explore veteran and nonveteran perceptions of the impact of their occupation on their psychological well‐being later in life.

Methods

Twenty‐five veterans (≥65 y); 25 nonveterans (≥65 y); 10 veterans with diagnoses of mental health issues (≥65 y); and a close companion of all participants (≥18 y, spouse, child, and close friend) were recruited. Using a qualitative approach, participants completed semistructured qualitative interviews with measures of psychological adjustment used to describe the sample.

Results

Veterans were found to experience higher levels of workplace stress and trauma exposure compared with nonveterans. When such challenges were positively appraised, veterans described increased confidence and resilience. Social support in response to occupational stress was central to veteran and nonveteran well‐being, especially for those with mental health problems. Nonetheless, providing support was challenging for close companions, with many feeling overwhelmed and requiring additional guidance from the veteran's clinical care team.

Conclusions

The findings delineate the impact of occupation on the well‐being of older veterans and nonveterans. The results illustrated the psychological support needs and formal guidance desired by veterans, nonveterans, and their families, which could ultimately improve coping of both the individual and family.
Fear of falling: A manifestation of executive dysfunction?
Authors: Peeters Geeske , Feeney Joanne , Carey Daniel , Kennelly Sean , Kenny Rose Anne
Published: May 2019

Objective

Fear of falling (FoF) may be an early marker of decline in global cognitive functioning, but associations with specific domains of cognitive functioning are unclear. The aim was to examine associations between FoF and 4‐year decline in memory, processing speed, and executive functioning in adults aged 50 years and older.

Methods

Data were from 5174 participants (mean age = 62.6 ± 8.9 years, range = 50‐91, 54.5% female) in The Irish Longitudinal Study on Ageing, a population‐based study.

Measurements

FoF was self‐reported in 2009 to 2011. Immediate and delayed recall, Colour Trails 1 and 2, choice reaction time, sustained attention to response task, and verbal fluency were measured in 2009 to 2011 and 2014 to 2015. Prospective associations between FoF and domains of cognitive functioning were examined using linear mixed modelling. Adjustment was made for demographic and health factors. Interactions with age were examined.

Results

In 2009 to 2011, 20.6% of participants reported FoF. No statistically significant interaction of FoF with age was found for any of the associations (P ≥ .06). Participants with FoF had greater decline on delayed recall (B = −0.19; 95% CI, −0.32 to −0.06), verbal fluency (B = −0.52; 95% CI, −0.88 to −0.18); and the ln‐transformed scores for the Colour Trails 1 test (B = −0.04; 95% CI, −0.07 to −0.01) and the Colour Trails 2 test (B = −0.04; 95% CI, −0.06 to −0.02) than participants without FoF. No statistically significant associations were found for any of the other outcomes.

Conclusions

FoF may be an indicator of decline in domains of cognitive functioning, particularly those related to executive function and processing speed. However, studies with longer follow‐up and/or higher average age are required to confirm this.
An innovative reconstruction procedure of total nasal resurfacing with a bipedicled propeller perforator flap
Authors: de Bonnecaze Guillaume , Chaput Benoit
Published: May 2019

Background

A forehead frontal flap is the treatment of choice for complex nasal defects. However, in patients with contra indications for such frontal flaps, few alternatives are available.

Methods

We developed a three‐stage, nasal reconstruction procedure using a bipedicled, propeller perforator flap based on the modiolus perforators. Here, we describe the flap, the harvesting thereof, and the 6‐month outcomes after placement.

Results

The flap did not exhibit any sign of necrosis or congestion. Six months after reconstruction, the patient had not suffered any esthetic or functional sequela.

Conclusion

Although the indications for our new flap are less numerous than those for a frontal flap, our flap is a useful alternative when frontal flap placement is not feasible (or the patient refuses such a flap) and when placement of a free flap is too risky.
Assessment of quality and consistency of monoclonal antibodies for CB1 and CB2 in head and neck squamous cell carcinoma
Authors: Daniels Kelly E. , Luginbuhl Adam J. , Mardekian Stacey K. , Cognetti David M. , Curry Joseph M. , South Andrew P.
Published: May 2019

Background

Marijuana has numerous roles as an agonist in the endocannabinoid signaling system (ESS). This study evaluated monoclonal antibodies across experimental techniques to establish a framework for studying ESS receptors, CB1 and CB2.

Methods

Tissue from five patients with head and neck cancer were used to generate cell lines and formalin‐fixed paraffin‐embedded (FFPE) sections, which were analyzed by western blot (WB), immunohistochemistry (IHC), and immunofluorescence (IF). Subgroup analysis was performed on FFPE sections from 8 marijuana users and 10 controls by IHC. Results were compared across methods for consistency.

Results

In all patients, WB and IF were CB1 positive, whereas IHC was negative. Select samples were CB2 positive by WB, but failed IF and IHC applications. In subgroup analysis, 1 of 8 users and 3 of 10 nonusers were CB1 positive.

Conclusions

Interpretation of CB1/CB2 antibody data should be performed cautiously and confirmation of findings across multiple experimental methods is recommended.
Prediction of survival with combining quantitative 18F‐FDG PET/CT and DW‐MRI parameters in sinonasal malignancies
Authors: Ozturk Kerem , Gencturk Mehmet , Caicedo‐Granados Emiro , Li Faqian , Cayci Zuzan
Published: May 2019

Background

We aimed to establish the prognostic value of 18F‐fluoro‐deoxy‐glucose positron emission/CT (18F‐FDG PET/CT) and diffusion‐weighted (DW) MRI in determining overall survival (OS), progression‐free survival (PFS), and distant metastasis‐free survival (DMFS) of sinonasal malignancies.

Methods

Sixty‐eight patients with sinonasal cancer who underwent both pretreatment 18F‐FDG PET/CT scan and head‐neck MRI from January 2009 through August 2017 were retrospectively reviewed. Kaplan‐Meier survival analysis of 18F‐FDG PET/CT and DW‐MRI parameters were performed for OS, PFS, and DMFS.

Results

Cox regression analysis determined that all the quantitative 18F‐FDG PET/CT and DW‐MRI parameters were independently correlated with PFS, DMFS, and OS (P < .05). After controlling for imaging variables, perineural invasion (P = .02) and ill‐defined margin (P = .02) were found to be significantly correlated with shorter OS; while the perineural invasion was significantly correlated with shorter PFS (P = .02).

Conclusions

The pretreatment DW‐MRI and 18F‐FDG PET/CT parameters could be substantial surrogate markers for sinonasal malignancies.
Fecal Microbial Transplant Capsules Are Safe in Hepatic Encephalopathy: A Phase 1, Randomized, Placebo‐Controlled Trial
Authors: Bajaj Jasmohan S. , Salzman Nita H. , Acharya Chathur , Sterling Richard K. , White Melanie B. , Gavis Edith A. , Fagan Andrew , Hayward Michael , Holtz Mary L. , Matherly Scott , Lee Hannah , Osman Majdi , Siddiqui Mohammad S. , Fuchs Michael , Puri Puneet , Sikaroodi Masoumeh , Gillevet Patrick M.
Published: May 2019

Hepatic encephalopathy (HE) can cause major morbidity despite standard of care (SOC; rifaximin/lactulose). Fecal microbial transplant (FMT) enemas postantibiotics are safe, but the effect of FMT without antibiotics using the capsular route requires investigation. The aim of this work was to determine the safety, tolerability, and impact on mucosal/stool microbiota and brain function in HE after capsular FMT in a randomized, single‐blind, placebo‐controlled clinical trial in Virginia. Patients with cirrhosis with recurrent HE with MELD (Model for End‐Stage Liver Disease) <17 on SOC were randomized 1:1 into receiving 15 FMT capsules versus placebo from a single donor enriched in Lachnospiraceae and Ruminococcaceae. Endoscopies with duodenal and sigmoid biopsies, stool analysis, cognition, serum lipopolysaccharide‐binding protein (LBP), and duodenal antimicrobial peptide (AMP) expression at baseline were used. Clinical follow‐up with SOC maintenance was performed until 5 months. FMT‐assigned patients underwent repeat endoscopies 4 weeks postenrollment. Twenty subjects on lactulose/rifaximin were randomized 1:1. MELD score was similar at baseline (9.6 vs. 10.2) and study end (10.2 vs. 10.5). Six patients in the placebo group required hospitalizations compared to 1 in FMT, which was deemed unrelated to FMT. Infection/HE episodes were similar between groups. Baseline microbial diversity was similar in all tissues between groups. Post‐FMT, duodenal mucosal diversity (P = 0.01) increased with higher Ruminococcaceae and Bifidobacteriaceae and lower Streptococcaceae and Veillonellaceae. Reduction in Veillonellaceae were noted post‐FMT in sigmoid (P = 0.04) and stool (P = 0.05). Duodenal E‐cadherin (P = 0.03) and defensin alpha 5 (P = 0.03) increased whereas interleukin‐6 (P = 0.02) and serum LBP (P = 0.009) reduced post‐FMT. EncephalApp performance improved post‐FMT only (P = 0.02). Conclusion: In this phase 1 study, oral FMT capsules are safe and well tolerated in patients with cirrhosis and recurrent HE. FMT was associated with improved duodenal mucosal diversity, dysbiosis, and AMP expression, reduced LBP, and improved EncephalApp performance. Further studies are needed to prove efficacy.
Activation of Pregnane X Receptor Sensitizes Mice to Hemorrhagic Shock–Induced Liver Injury
Authors: Xie Yang , Xu Meishu , Deng Meihong , Li Zhigang , Wang Pengcheng , Ren Songrong , Guo Yan , Ma Xiaochao , Fan Jie , Billiar Timothy R. , Xie Wen
Published: May 2019

Hemorrhagic shock (HS) is a life‐threatening condition associated with tissue hypoperfusion and often leads to injury of multiple organs including the liver. Pregnane X receptor (PXR) is a species‐specific xenobiotic receptor that regulates the expression of drug‐metabolizing enzymes (DMEs) such as the cytochrome P450 (CYP) 3A. Many clinical drugs, including those often prescribed to trauma patients, are known to activate PXR and induce CYP3A. The goal of this study is to determine whether PXR plays a role in the regulation of DMEs in the setting of HS and whether activation of PXR is beneficial or detrimental to HS‐induced hepatic injury. PXR transgenic, knockout, and humanized mice were subject to HS, and the liver injury was assessed histologically and biochemically. The expression and/or activity of PXR and CYP3A were manipulated genetically or pharmacologically in order to determine their effects on HS‐induced liver injury. Our results showed that genetic or pharmacological activation of PXR sensitized wild‐type and hPXR/CYP3A4 humanized mice to HS‐induced hepatic injury, whereas knockout of PXR protected mice from HS‐induced liver injury. Mechanistically, the sensitizing effect of PXR activation was accounted for by PXR‐responsive induction of CYP3A and increased oxidative stress in the liver. The sensitizing effect of PXR was attenuated by ablation or pharmacological inhibition of CYP3A, treatment with the antioxidant N‐acetylcysteine amide, or treatment with a PXR antagonist. Conclusion: We have uncovered a function of PXR in HS‐induced hepatic injury. Our results suggest that the unavoidable use of PXR‐activating drugs in trauma patients has the potential to exacerbate HS‐induced hepatic injury, which can be mitigated by the coadministration of antioxidative agents, CYP3A inhibitors, or PXR antagonists.
Selective Liver Estrogen Receptor α Modulation Prevents Steatosis, Diabetes, and Obesity Through the Anorectic Growth Differentiation Factor 15 Hepatokine in Mice
Authors: Guillaume Maeva , Riant Elodie , Fabre Aurélie , Raymond‐Letron Isabelle , Buscato Melissa , Davezac Morgane , Tramunt Blandine , Montagner Alexandra , Smati Sarra , Zahreddine Rana , Palierne Gaëlle , Valera Marie‐Cécile , Guillou Hervé , Lenfant Françoise , Unsicker Klaus , Metivier Raphaël , Fontaine Coralie , Arnal Jean‐François , Gourdy Pierre
Published: May 2019

Hepatocyte estrogen receptor α (ERα) was recently recognized as a relevant molecular target for nonalcoholic fatty liver disease (NAFLD) prevention. The present study defined to what extent hepatocyte ERα could be involved in preserving metabolic homeostasis in response to a full (17β‐estradiol [E2]) or selective (selective estrogen receptor modulator [SERM]) activation. Ovariectomized mice harboring a hepatocyte‐specific ERα deletion (LERKO mice) and their wild‐type (WT) littermates were fed a high‐fat diet (HFD) and concomitantly treated with E2, tamoxifen (TAM; the most used SERM), or vehicle. As expected, both E2 and TAM prevented all HFD‐induced metabolic disorders in WT mice, and their protective effects against steatosis were abolished in LERKO mice. However, while E2 still prevented obesity and glucose intolerance in LERKO mice, hepatocyte ERα deletion also abrogated TAM‐mediated control of food intake as well as its beneficial actions on adiposity, insulin sensitivity, and glucose homeostasis, suggesting a whole‐body protective role for liver‐derived circulating factors. Moreover, unlike E2, TAM induced a rise in plasma concentration of the anorectic hepatokine growth differentiation factor 15 (Gdf15) through a transcriptional mechanism dependent on hepatocyte ERα activation. Accordingly, ERα was associated with specific binding sites in the Gdf15 regulatory region in hepatocytes from TAM‐treated mice but not under E2 treatment due to specific epigenetic modifications. Finally, all the protective effects of TAM were abolished in HFD‐fed GDF15‐knockout mice. Conclusion: We identified the selective modulation of hepatocyte ERα as a pharmacologic strategy to induce sufficient anorectic hepatokine Gdf15 to prevent experimental obesity, type 2 diabetes, and NAFLD.
Prediction of local heat transfer characteristics of dilute gas‐solid flows through an adiabatic, horizontal pipe
Authors: Patro Brundaban , Kiran Kumar K. , Jaya Krishna D.
Published: May 2019

The local heat transfer characteristics of gas‐solid flows through an adiabatic, horizontal pipe are numerically studied using the two‐fluid model of Ansys Fluent 15. First, the model is validated with the experimental results available in the literature for the air temperature and average Nusselt number. Then, the local heat transfer characteristics of gas‐solid flows, such as temperature profiles of gas and solid, gas‐solid Nusselt number, logarithmic mean temperature difference, and effectiveness of gas and solid, are studied by changing different parameters (gas velocities 15‐24 m/s; inlet solid loading ratios 0.1‐1; particle diameters 100‐400 µm). It is observed that increasing the particle diameter and inlet gas velocity increases the gas temperature and decreases the solid temperature, increases the logarithmic mean temperature difference, and decreases the thermal effectiveness of gas and solid. However, increasing the solid loading ratio decreases the gas and solid temperatures, decreases the logarithmic mean temperature difference, and increases the thermal effectiveness of gas and decreases the thermal effectiveness of solid. Moreover, increasing the particle diameter decreases the gas‐solid Nusselt number, whereas increasing the solid loading ratio and inlet gas velocity increase the gas‐solid Nusselt number.
Meta‐analysis of 16 studies of the association of alcohol with colorectal cancer
Authors: McNabb Sarah , Harrison Tabitha A. , Albanes Demetrius , Berndt Sonja I. , Brenner Hermann , Caan Bette J. , Campbell Peter T. , Cao Yin , Chang‐Claude Jenny , Chan Andrew , Chen Zhengyi , English Dallas R. , Giles Graham G. , Giovannucci Edward L. , Goodman Phyllis J. , Hayes Richard B. , Hoffmeister Michael , Jacobs Eric J. , Joshi Amit D. , Larsson Susanna C. , Le Marchand Loïc , Li Li , Lin Yi , Männistö Satu , Milne Roger L. , Nan Hongmei , Newton Christina C. , Ogino Shuji , Parfrey Patrick S. , Petersen Paneen S. , Potter John D. , Schoen Robert E. , Slattery Martha L. , Su Yu‐Ru , Tangen Catherine M. , Tucker Thomas C. , Weinstein Stephanie J. , White Emily , Wolk Alicja , Woods Michael O. , Phipps Amanda I. , Peters Ulrike
Published: May 2019

Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol–CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case‐control and 11 nested case‐control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study‐specific results were pooled using fixed‐effects meta‐analysis. Compared to non‐/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88–0.98, p = 0.005), heavy drinking (2–3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99–1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11–1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J‐shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.
Maternal sepsis is an evolving challenge
Authors: Turner Michael J.
Published: May 2019

Despite major advances in the last century, particularly in high resource settings, maternal sepsis remains a common and potentially preventable cause of direct maternal death globally. A barrier to further progress has been the lack of consensus on the definition of maternal sepsis. Publications from two recent multidisciplinary consensus conferences, one on sepsis in the non‐pregnant adult and the other on sepsis in the pregnant woman, concluded that the criteria for diagnosing sepsis should be clinically‐based, applicable at the bedside, and should not be laboratory‐based. Informed by reviews of the evidence, in 2017 WHO published a new definition of maternal sepsis based on the presence of suspected or confirmed infection. It also announced a Global Maternal and Neonatal Sepsis Initiative to identify the diagnostic criteria for the early identification, epidemiology, and disease classification of maternal sepsis. Standardizing the criteria for maternal sepsis optimizes clinical audit and research. It may facilitate the evaluation of the role of different clinical parameters and biomarkers in the diagnosis, earlier recognition and management of maternal infection and sepsis. Further work is required to develop an international consensus on the criteria for diagnosing maternal sepsis and any associated organ dysfunction.
Identification of key transcription factors in endometrial cancer by systems bioinformatics analysis
Authors: Song Yong , Chen Qiu‐Tong , He Qi‐Qiang
Published: May 2019

Endometrial cancer (EC) is one of the most common malignant diseases worldwide. Although many studies have been performed on EC, a systems analysis between transcription factors (TFs) and EC relationship remains poorly characterized. Here, we present a systems bioinformatics analysis of TFs in EC patient samples to identify key TFs in EC. First, dysregulated and survival‐related TFs were identified in EC using data from The Cancer Genome Atlas database and Gene Expression Omnibus. Second, we investigated the mechanisms of dysregulated TFs and tested whether their expression is correlated with prognosis of EC. Finally, we addressed new perspectives in EC biomarker research, including comprehensive knowledge of previously suggested candidate biomarkers in conjunction with novel mass spectrometry‐based proteomic technologies with enhanced sensitivity and specificity not yet applied to EC studies, enabling a directed clinical perspective of the study design. Our study identified three promising TFs, E2F1, HMGA1, and PGR, which closely correlate with EC. Although treatments targeting TFs are not always efficient, these TFs may be useful as biomarkers for the diagnosis and prognosis of EC. Furthermore, we found that these dysregulated TFs and their target genes are primarily involved in the cell cycle and may promote endometrial carcinoma occurrence and development. Using integrated bioinformatic analysis, we identified candidate genes and pathways in EC, which could improve our understanding of the etiology and underlying molecular events of EC. Furthermore, these candidate genes and pathways could be therapeutic targets for EC.
The association between three AXIN2 variants and cancer risk
Authors: Dai Feng , Zhu Li‐Jie , Zhang Wei , Mi Yuan‐Yuan , Sun He‐Yun , Zhang Li‐Feng , Yue Chuang , Wu Xing‐Yu , Zuo Li , Bai Yu
Published: May 2019

Plenty of epidemiological studies have assessed the effects of AXIN2 polymorphisms on the risk of developing cancer, but the available results were somewhat inconclusive. Odds ratios (ORs) with 95% confidence intervals (CIs) were utilized to investigate the relationship between three AXIN2 variants (rs2240308 C/T, rs1133683 C/T, and rs4791171 A/G) and overall cancer susceptibility. In silico tools were undertaken to investigate the correlation of AXIN2 expression with cancer risk and survival time. Furthermore, we explored the serum expression of AXIN2 by enzyme‐linked immunosorbent assay. A total of 4167 cancer patients and 3515 control subjects were evaluated. The overall results demonstrated that there was no major association of these polymorphisms on cancer risk. However, stratified analysis by cancer type showed evidence that rs2240308 C/T polymorphism had a lower risk in lung cancer (OR, 0.76; 95% CI, 0.63‐0.92; Pheterogeneity = 0.865) and prostate cancer (OR, 0.54; 95% CI, 0.35‐0.84; Pheterogeneity = 0.088) by heterozygote comparison. Similar results were indicated in Asian descendants and population‐based studies. In silico analysis showed evidence that AXIN2 expressions in lung cancer and prostate cancer were lower than that in normal counterpart. High expression of AXIN2 may have longer overall survival time than low expression group for lung cancer participants. In addition, individuals who were CC/TC carriers had a higher serum expression level than TT carriers. In conclusion, this pooled analysis suggested that AXIN2 rs2240308 C/T variant may decrease both lung and prostate cancer susceptibility, particularly in Asian descendants and population‐based studies. Future large scale and well‐designed research are required to validate these effects in more detail.
From red vegetables to sexuality: Resymbolizing the meaning of concrete thought in eating disorders
Authors: Pearlman Barbara
Published: May 2019

This paper introduces and describes the theory and practice of a novel treatment approach to eating disorders—internal language enhancement therapy (ILET)—illustrated with a case study. This treatment approach is informed by the neurobiology of emotional processing integrated with elements of psychoanalytic theory and practice, early maternal preoccupation, development of the self, early right hemisphere language development, and techniques from cognitive behavioral therapy. ILET is based on the Discontinuous Model of Neural Emotional Processing, which means that emotions are processed in the brain either symbolically or concretely. The aim of ILET is to open up and reinforce the underused brain pathway to the symbolic functions by forensically working back to and accurately identifying the emotional material that triggers the concrete state. When the emotional trigger is identified it is explored using symbolic and metaphoric language that reconnects the patient to the symbolic state. ILET posits that eating disorders only appear in the concrete state.
The role of therapist MI skill and client change talk class membership predicting dual alcohol and sex risk outcomes
Authors: Janssen Tim , Magill Molly , Mastroleo Nadine R. , Laws M. Barton , Howe Chanelle J. , Walthers Justin W. , Monti Peter M. , Kahler Christopher W.
Published: May 2019

Objective

We investigated the technical model of motivational interviewing (MI) in a dual‐outcome intervention (i.e., alcohol, sexual risk; N = 164; 57% female).

Method

We identified latent classes of client change statements, based on the proportion of change talk (CT) over the session. We then examined whether outcomes were related to CT class, and whether the relations between MI skill and outcomes varied by CT class.

Results

We found three classes of alcohol‐CT and two classes of sexual risk‐CT. While CT class membership did not predict outcomes directly, greater therapist MI‐consistent skill was associated with fewer heavy drinking days in the increasing alcohol‐CT class. For sexual risk outcomes, therapist MI‐consistent skill was associated with reduced odds of condomless sex for the low sexual risk‐CT class.

Conclusions

The relation of therapist MI consistency to outcomes appears to be a function of client CT during the session.
Transfer of baseline reject control to transitivity trials and its effect on equivalence class formation
Authors: Plazas Elberto A.
Published: May 2019

This study explored the role of baseline reject control on transitivity responding. In Experiment 1, participants learned to respond to a baseline of arbitrary AB and AC conditional relations, and then they were exposed to transitivity‐like BC and CB trials in which the correct comparison stimulus was replaced by a novel stimulus (D). Five of 10 participants selected stimulus D, but only 1 showed expansion of the baseline stimulus classes to include the D stimuli. In Experiment 2, the emergence of symmetry and transitivity from baseline relations was assessed before participants were exposed to the transitivity‐like trials. Six of 8 participants who showed emergence of equivalence relations selected the D stimuli on transitivity‐like trials and provided evidence that baseline classes expanded to include these stimuli. In Experiment 3, these 6 participants selected novel stimuli (E) in additional transitivity‐like trials, and all showed that the E stimuli had become members of the previously established classes, which now comprised 5 members. A route for the emergence of transitivity by way of the transfer of baseline between‐classes reject control is discussed.
Recent progress in allosteric modulators for GluN2A subunit and development of GluN2A‐selective nuclear imaging probes
Authors: He Yingfang , Mu Linjing , Ametamey Simon M. , Schibli Roger
Published: May 2019

N‐methyl‐D‐aspartate (NMDA) receptors play key roles in physiology by regulating the synaptic plasticity and the cellular mechanism involved in learning and memory. The GluN2A subunit is the most abundant expression of NMDA receptors in mature brain, and its dysfunction has been implicated in various neurological disorders. However, the function of GluN2A subunit in physiological and pathological conditions is not yet completely unveil due to the lack of subunit‐selective ligands, including specific positron emission tomography (PET)/single photon emission computed tomography (SPECT) imaging probes. In this review, recent progresses in understanding its pathophysiological role, the structure‐activity relationship, and the postulated mechanisms of novel GluN2A ligands as well as status of molecular imaging probes for PET are summarized.
Synthesis of 18F‐radiolabeled diphenyl gallium dithiosemicarbazone using a novel halogen exchange method and in vivo biodistribution
Authors: Venkatachalam Taracad K. , Stimson Damion H.R. , Bhalla Rajiv , Mardon Karine , Bernhardt Paul V. , Reutens David C.
Published: May 2019

18F‐radiolabeled diphenyl gallium thiosemicarbazone was prepared by [18F] fluoride exchange of a nitrato anion under mild conditions. The diphenyl gallium thiosemicarbazone chloride is easily prepared in gram quantities and can be used at room temperature in the presence of oxygen. The corresponding nitrate complex is prepared using silver nitrate in methanol solvent and can be stored under nitrogen for weeks before radiolabeling. The biodistribution of this new tracer was studied in mice using positron emission tomography (PET).
Overview of established and emerging immunohistochemical biomarkers and their role in correlative studies in MRI
Authors: Alvi Emaan , Gupta Rajarsi , Borok Raphael Z. , Escobar‐Hoyos Luisa , Shroyer Kenneth R.
Published: May 2019

Clinical practice in radiology and pathology requires professional expertise and many years of training to visually evaluate and interpret abnormal phenotypic features in medical images and tissue sections to generate diagnoses that guide patient management and treatment. Recent advances in digital image analysis methods and machine learning have led to significant interest in extracting additional information from medical and digital whole‐slide images in radiology and pathology, respectively. This has led to significant interest and research in radiomics and pathomics to correlate phenotypic features of disease with image analytics in order to identify image‐based biomarkers. The expanding role of big data in radiology and pathology parallels the development and role of immunohistochemistry (IHC) in the daily practice of pathology. IHC methods were initially developed to provide additional information to help classify tumors and then transformed into an indispensable tool to guide treatment in many types of cancer. IHC markers are used in daily practice to identify specific types of cells and highlight their distributions in tissues in order to distinguish benign from neoplastic cells, determine tumor origin, subclassify neoplasms, and support and confirm diagnoses. In this regard, radiomics, pathomics, and IHC methods are very similar since they enable the extraction of image‐based features to characterize various properties of diseases. Due to the dramatic advancements in recent radiomics research, we provide a brief overview of the role of established and emerging IHC biomarkers in various tumor types that have been correlated with radiologic biomarkers to improve diagnostic accuracy, predict prognosis, guide patient management, and select treatment strategies.

Level of Evidence: 5

Technical Efficacy: Stage 3

J. Magn. Reson. Imaging 2020;51:341–354.
Cerebral circulation time derived from fMRI signals in large blood vessels
Authors: Yao Jinxia (Fiona) , Wang James H. , Yang Ho‐Ching (Shawn) , Liang Zhenhu , Cohen‐Gadol Aaron A. , Rayz Vitaliy L. , Tong Yunjie
Published: May 2019

Background

The systemic low‐frequency oscillation (sLFO) functional (f)MRI signals extracted from the internal carotid artery (ICA) and the superior sagittal sinus (SSS) are found to have valuable physiological information.

Purpose

1) To further develop and validate a method utilizing these signals to measure the delay times from the ICAs and the SSS. 2) To establish the delay time as an effective perfusion biomarker that associates with cerebral circulation time (CCT). 3) To explore within subject variations, and the effects of gender and age on the delay times.

Study Type

Prospective.

Subjects

In all, 100 healthy adults (Human Connectome Project [HCP], age range 22–36 years, 54 females and 46 males), 56 healthy children (Adolescent Brain Cognitive Development project) were included.

Field Strength/Sequence

Echo planar imaging (EPI) sequence at 3T.

Assessment

The sLFO fMRI signals from the ICAs and the SSSs were extracted from the resting state fMRI data. The maximum cross‐correlation coefficients and their corresponding delay times were calculated. The gender and age differences of delay times were assessed statistically.

Statistical Tests

T‐tests were conducted to measure the gender differences. The Kruskal–Wallis test was used to detect age differences.

Results

Consistent and robust results were found from 80% of the 400 HCP scans included. Negative correlations (–0.67) between the ICA and the SSS signals were found with the ICA signal leading the SSS signal by ∼5 sec. Within subject variation was 2.23 sec at the 5% significance level. The delay times were not significantly different between genders (P = 0.9846, P = 0.2288 for the left and right ICA, respectively). Significantly shorter delay times (4.3 sec) were found in the children than in the adults (P < 0.01).

Data Conclusion

We have shown that meaningful perfusion information (ie, CCT) can be derived from the sLFO fMRI signals of the large blood vessels.

Level of Evidence: 1

Technical Efficacy Stage: 1

J. Magn. Reson. Imaging 2019;50:1504–1513.
Changes in extreme temperature and precipitation indices: Using an innovative daily homogenized database in Israel
Authors: Yosef Yizhak , Aguilar Enric , Alpert Pinhas
Published: May 2019

This study examines the 1950–2017 temporal changes in climate extremes in Israel, which is located in the East Mediterranean (EM), a region which suffers from a scarcity of long and reliable datasets. It is well known that most long‐term records are affected by artificial shifts most commonly caused by station relocation, instrumental modification and local environmental changes. Therefore, for the first time, a thorough homogenization (detection and correction) routine was developed and implemented in the long‐term records. Consequently, a new daily adjusted dataset has been generated, including 34 temperature stations and 60 precipitation stations. Based on this comprehensive dataset, 38 extreme indices recommended by the Expert Team on Climate Change Detection and the Expert Team on Sector‐specific Climate Indices have been calculated. These indices will help various sectors to plan properly mitigation actions and adaptation for climate change, in addition to facilitating future studies for the EM. The results showed highly significant changes in temperature extremes associated with warming, especially for those indices derived from the daily minimum temperature (TN, 1950–2017), whereas the maximum temperature (TX) exhibited a similar increasing magnitude of the TN (~0.55°C/decade) in the last 30 years. The warming trends, which are non‐monotonic, seem to have been particularly strong since the early 1990s. The coastal area is characterized by higher heat stress during the nighttime, while mountains exhibit a strong tendency towards increasing temperatures during the noon hours. A reduction in the total precipitation amount and in the number of wet days with a tendency towards more intense wet days was found. Although all the regional trends of the precipitation indices were not statistically significant (p≤ .05), they showed a fine spatial coherence.
Patient‐Specific Functional Analysis: The Key to the Next Revolution Towards the Treatment of Hip and Knee Osteoarthritis
Authors: Astephen Wilson Janie L. , Lamontagne Mario , Wilson David R. , Beaulé Paul E. , Mwale Fackson , Yee Albert
Published: May 2019

Lower extremity joint arthroplasty surgery remains one of the most successful interventions in orthopaedics. While improvements in patient mobility and physical functioning following surgery are well‐documented, there remains significant post‐operative functional deficits in many patients. This highlights a need and an opportunity towards improving functional and patient‐reported outcomes of arthroplasty surgery. This review summarizes key opportunities arising from the recent 2018 Orthopaedic Research Society Meeting in New Orleans, USA. In this review, the Canadian Orthopaedic Research Society (i.e., CORS) highlights key research advances, case examples, scientific messages, and personalized medical care approaches toward improving physical functioning in our knee and hip joint arthroplasty patients. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1754–1759, 2019
Effects of Surgical Angiogenesis on Segmental Bone Reconstruction With Cryopreserved Massive‐Structural Allografts in a Porcine Tibia Model
Authors: Visser Noortje J. , Rezaie Elisa S. , Friedrich Patricia F. , Kotsougiani Dimitra , Shin Alexander Y. , Bishop Allen T.
Published: May 2019

Cryopreserved bone allografts (CBA) used to reconstruct segmental bone defects provide immediate structural stability, but are vulnerable to infection, non‐union and late stress fracture as the majority of the allograft remains largely avascular. We sought to improve the bone vascularity and bone formation of CBAs by surgical angiogenesis with an implanted arteriovenous (AV) bundle, using a porcine tibial defect model. Cryopreserved tibial bone allografts were transplanted in swine leukocyte antigen (SLA) mismatched Yucatan minipigs to reconstruct a 3.5 cm segmental tibial defect. A cranial tibial AV‐bundle was placed within its intramedullary canal to induce angiogenesis. The AV bundle was patent in eight pigs and ligated in a control group of eight pigs. At 20 weeks neo‐angiogenesis was evaluated by micro‐angiography. Bone formation was measured by quantitative histomorphometry and micro‐computed tomography. Seven of eight AV‐bundles in the revascularized group were patent. One had thrombosed due to allograft displacement. Total vascular volume was higher in the revascularized allografts compared to the ligated group (p = 0.015). Revascularized allografts had increased levels of bone formation on the allograft endosteal surface compared to the ligated control group (p = 0.05). Surgical angiogenesis of porcine tibial CBAs by intramedullary implantation of an AV‐bundle creates an enhanced autogenous neoangiogenic circulation and accelerates active bone formation on allograft endosteal surfaces. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1698–1708, 2019