bluuebunny/crossref_metadata_2025 huggingface dataset:
How should information technology be covered in the accounting program?
Authors: Boulianne Emilio
Published: November 2016

Professional accounting associations, business schools, and accounting professors are increasingly faced with an important question: Which information technology (IT) competencies should be developed in accounting programs to train skilled professional accountants? Key references in accounting education show that advanced‐level training in IT is very important for accountants’ careers. Through content analysis, I investigate how Canadian CPAs are trained in IT. Results indicate that, postmerger, IT has lost ground in the CPA program. This could be mainly due to: (a) a larger coverage in finance, strategy, and governance topics; (b) challenges to promote and teach IT in terms of course development; and (c) a lack of recognition of and incentives for academic work on IT. Compared to some key players in accounting education, it appears that Canada has taken a different route with regard to the required IT competencies. Copyright © 2016 ASAC. Published by John Wiley & Sons, Ltd.
The prevalence and management of angina among patients with chronic coronary artery disease across US outpatient cardiology practices: insights from the Angina Prevalence and Provider Evaluation of Angina Relief (APPEAR) study
Authors: Kureshi Faraz , Shafiq Ali , Arnold Suzanne V. , Gosch Kensey , Breeding Tracie , Kumar Ashwath S. , Jones Philip G. , Spertus John A.
Published: November 2016

Although eliminating angina is a primary goal in treating patients with chronic coronary artery disease (CAD), few contemporary data quantify prevalence and severity of angina across US cardiology practices. The authors hypothesized that angina among outpatients with CAD managed by US cardiologists is low and its prevalence varies by site. Among 25 US outpatient cardiology clinics enrolled in the American College of Cardiology Practice Innovation and Clinical Excellence (PINNACLE) registry, we prospectively recruited a consecutive sample of patients with chronic CAD over a 1‐ to 2‐week period at each site between April 2013 and July 2015, irrespective of the reason for their appointment. Eligible patients had documented history of CAD (prior acute coronary syndrome, prior coronary revascularization procedure, or diagnosis of stable angina) and ≥1 prior office visit at the practice site. Angina was assessed directly from patients using the Seattle Angina Questionnaire Angina Frequency score. Among 1257 patients from 25 sites, 7.6% (n = 96) reported daily/weekly, 25.1% (n = 315) monthly, and 67.3% (n = 846) no angina. The proportion of patients with daily/weekly angina at each site ranged from 2.0% to 24.0%, but just over half (56.3%) were on ≥2 antianginal medications, with wide variability across sites (0%–100%). One‐third of outpatients with chronic CAD managed by cardiologists report having angina in the prior month, and 7.6% have frequent symptoms. Among those with frequent angina, just over half were on ≥2 antianginal medications, with wide variability across sites. These findings suggest an opportunity to improve symptom control.
Immune by Heart: Unexpected Observations Inspiring Perspective Therapeutic/Preventive Strategies against Cancer
Authors: Minutolo Filippo
Published: November 2016

We often overlook ordinary events that take place right in front of our eyes. However, such events might be inspiring sources of revolutionary scientific discovery. Simple observations, such as those regarding the substantial immunity of the heart to cancer or the noninvasive behavior of plant tumors, are just the tips of icebergs hiding profound mechanistic causes that deserve deeper investigation. Several current or unprecedented approaches aimed at improving both the prevention and treatment of tumors are discussed on these bases herein. This viewpoint is not intended to give definitive answers, but rather to provide cues for discussion and motivation to pursue unexplored and accessible strategies to fight cancer.
Preoperative assessment of lymph node metastasis in endometrial cancer: A Korean Gynecologic Oncology Group study
Authors: Kang Sokbom , Nam Joo‐Hyun , Bae Duk‐Soo , Kim Jae‐Weon , Kim Moon‐Hong , Chen Xiaojun , No Jae‐Hong , Lee Jong‐Min , Kim Jae‐Hoon , Watari Hidemich , Kim Seok Mo , Kim Sung Hoon , Seong Seok Ju , Kim Ki Tae , Kim Seung Cheol , Kim Jong‐Hyeok , Lim Myung‐Cheol , Lee Jung‐Yun , Ryu Sang‐Young , Yang Bingyi , Kim Byoung‐Gie
Published: November 2016

BACKGROUND

Previously proposed criteria for preoperatively identifying endometrial cancer patients at low risk for lymph node metastasis remain to be verified. For this purpose, a prospective, multicenter observational study was performed.

METHODS

Eligible patients with histologically confirmed endometrial cancer underwent magnetic resonance imaging (MRI) and serum cancer antigen 125 (CA 125) testing before surgery. The following criteria were used to identify low‐risk patients: 1) endometrioid‐type cancer, 2) no evidence of deep myometrial invasion on MRI, 3) no enlarged lymph nodes on MRI, 4) no suspicious metastasis out of the uterine corpus, and 5) serum CA 125 levels less than 35 U/mL. Systematic pelvic and/or para‐aortic lymphadenectomy was performed for all patients. The primary endpoint was estimation of the negative predictive value (NPV).

RESULTS

From January 2012 to December 2014, 529 patients from 20 hospitals in 3 Asian countries were consecutively enrolled. According to our criteria, 272 patients (51.4%) were categorized into the low‐risk group. Fifty‐three of the 529 patients (10.0%) had lymph node metastases; these patients included 8 (2.9%) falsely categorized as low‐risk. The sensitivity and specificity of the criteria were 84.9% and 55.5%, respectively. The NPV of 97.1% was higher than the predefined target endpoint of 96%.

CONCLUSIONS

The low‐risk criteria based on preoperative tests were confirmed to be reliable and accurate for identifying patients at low risk for lymph node metastasis. These criteria may facilitate patient counseling and surgical decision making. Cancer 2017;123:263–272. © 2016 American Cancer Society.
Second opinions from urologists for prostate cancer: Who gets them, why, and their link to treatment
Authors: Radhakrishnan Archana , Grande David , Mitra Nandita , Bekelman Justin , Stillson Christian , Pollack Craig Evan
Published: November 2016

BACKGROUND

Cancer patients are encouraged to obtain second opinions before starting treatment. Little is known about men with localized prostate cancer who seek second opinions, the reasons why, and the association with treatment and quality of care.

METHODS

We surveyed men who were diagnosed with localized prostate cancer in the greater Philadelphia area from 2012 to 2014. Men were asked if they obtained a second opinion from a urologist, and the reasons why. We used multivariable logistic regression models to evaluate the relationship between second opinions and definitive prostate cancer treatment and perceived quality of care.

RESULTS

A total of 2386 men responded to the survey (adjusted response rate, 51.1%). After applying exclusion criteria, the final analytic cohort included 2365 respondents. Of these, 40% obtained second opinions, most commonly because they wanted more information about their cancer (50.8%) and wanted to be seen by the best doctor (46.3%). Overall, obtaining second opinions was not associated with definitive treatment or perceived quality of cancer care. Men who sought second opinions because they were dissatisfied with their initial urologist were less likely to receive definitive treatment (odds ratio, 0.49; 95% confidence interval, 0.32‐0.73), and men who wanted more information about treatment were less likely to report excellent quality of cancer care (odds ratio, 0.70; 95% confidence interval, 0.49‐0.99) compared with men who did not receive a second opinion.

CONCLUSIONS

Although a large proportion of men with localized prostate cancer obtained a second opinion, the reasons for doing so were not associated with treatment choice or perceived quality of cancer care. Future study is needed to determine when second opinions contribute to increasing the value of cancer care. Cancer 2017;123:1027–34. © 2016 American Cancer Society.
Mesothelium expression of vascular cell adhesion molecule‐1 (VCAM‐1) is associated with an unfavorable prognosis in epithelial ovarian cancer (EOC)
Authors: Scalici Jennifer M. , Arapovic Sanja , Saks Erin J. , Atkins Kristen A. , Petroni Gina , Duska Linda R. , Slack‐Davis Jill K.
Published: November 2016

BACKGROUND

Mesothelium vascular cell adhesion molecule‐1 (VCAM‐1) expression in the metastatic epithelial ovarian cancer (EOC) microenvironment is induced by tumor and mediates tumor cell invasion. VCAM‐1 imaging suggests expression during treatment is an indicator of platinum resistance. Here, we assess the potential prognostic significance of mesothelium VCAM‐1 expression and prospectively evaluate whether soluble VCAM‐1 (sVCAM‐1) is a surrogate for mesothelium expression.

METHODS

A retrospective review of EOC patients was performed to evaluate outcomes with mesothelium VCAM‐1 expression determined by immunohistochemistry of peritoneum or omentum specimens. A prospective cohort of EOC patients was identified and followed through primary treatment. Serum for sVCAM‐1 evaluation, which was performed via enzyme‐linked immunosorbent assay, was collected before surgery or neoadjuvant chemotherapy and at each treatment cycle. Peritoneal specimens were obtained during debulking to assess mesothelial VCAM‐1 expression.

RESULTS

A retrospective review identified 54 advanced‐stage EOC patients. Patients expressing mesothelium VCAM‐1 had shortened overall survival (44 vs 79 months, P = 0.035) and progression‐free survival (18 vs 67 months, P = 0.010); the median time to platinum resistance was 36 months for VCAM‐1–expressing patients and not yet determined for the VCAM‐1–negative group. In our prospective observational cohort, 18 EOC patients completed primary treatment; 3 were negative for mesothelium VCAM‐1 expression, and sVCAM‐1 did not vary between groups.

CONCLUSIONS

Mesothelium VCAM‐1 expression is negatively associated with progression‐free and overall survival in EOC. This is especially compelling in light of previous data suggesting that persistent VCAM‐1 expression during treatment is an indicator of platinum resistance. Our pilot study had insufficient cases to determine whether sVCAM‐1 would substitute for mesothelium expression. Cancer 2017;123:977–84. © 2016 American Cancer Society.
Adjuvant chemotherapy versus chemoradiotherapy in the management of patients with surgically resected duodenal adenocarcinoma: A propensity score‐matched analysis of a nationwide clinical oncology database
Authors: Ecker Brett L. , McMillan Matthew T. , Datta Jashodeep , Lee Major K. , Karakousis Giorgos C. , Vollmer Charles M. , Drebin Jeffrey A. , Fraker Douglas L. , Roses Robert E.
Published: November 2016

BACKGROUND

To the authors' knowledge, optimal adjuvant approaches for resected duodenal adenocarcinoma are not well established. Given the significant risk of locoregional disease recurrence, there may be a subset of patients who demonstrate an improvement in overall survival (OS) from the addition of radiotherapy (chemoradiotherapy [CRT]) to an adjuvant chemotherapy regimen.

METHODS

Patients with resected, nonmetastatic duodenal adenocarcinoma who received chemotherapy (694 patients) or CRT (550 patients) were identified in the National Cancer Data Base (1998‐2012). Cox regression identified covariates associated with OS. The chemotherapy and CRT cohorts were matched (1:1) by propensity scores based on the likelihood of receiving CRT or the survival hazard from Cox modeling. OS was compared using Kaplan‐Meier estimates.

RESULTS

CRT was more frequently used for patients who underwent positive‐margin surgical resection (15.9% vs 9.1%; P<.001). At a median follow‐up of 79.2 months (interquartile range, 52.9‐114.9 months), the median OS of the propensity score‐matched cohort was 46.7 months (interquartile range, 18.9 months to not reached). No survival advantage was observed for patients who were treated with adjuvant CRT compared with those treated with adjuvant chemotherapy (median OS: 48.9 months vs 43.5 months [HR, 1.04; 95% confidence interval, 0.88‐1.22 (P = .669)]). CRT was not found to be associated with a significant improvement in the median OS after positive‐margin surgical resection (133 patients; 27.6 months vs 18.5 months [P = .210]) or in the presence of T4 classification (461 patients; 30.6 months vs 30.4 months [P = .844]) inadequate lymph node staging (584 patients; 40.5 months vs 43.2 months [P = .707]), lymph node positivity (647 patients; 38.3 months vs 34.1 months [P = .622]), or poorly differentiated histology (429 patients; 46.6 months vs 35.7 months [P = .434]).

CONCLUSIONS

The addition of radiation to adjuvant therapy does not appear to significantly improve survival, even in high‐risk cases. Cancer 2017;123:967–76. © 2016 American Cancer Society.
Trivium hardware implementations for power reduction
Authors: Mora‐Gutiérrez J. M. , Jiménez‐Fernández C.J. , Valencia‐Barrero M.
Published: November 2016

This paper describes the use of parallelization techniques to reduce dynamic power consumption in hardware implementations of the Trivium stream cipher. Trivium is a synchronous stream cipher based on a combination of three non‐linear feedback shift registers. In 2008, it was chosen as a finalist for the hardware profile of the eSTREAM project. So that their power consumption values can be compared and verified, the proposed low‐power Trivium designs were implemented and characterized in 350‐nm standard‐cell technology with both transistors and gate‐level models, in order to permit both electrical and logical simulations. The results show that the two designs decreased average power consumption by between 15% and 25% with virtually no performance loss and only a slight overhead (about 5%) in area. Copyright © 2016 John Wiley & Sons, Ltd.
Parental strategies used in the family meal session of family‐based treatment for adolescent anorexia nervosa: Links with treatment outcomes
Authors: White Hannah J. , Haycraft Emma , Madden Sloane , Rhodes Paul , Miskovic‐Wheatley Jane , Wallis Andrew , Kohn Michael , Meyer Caroline
Published: November 2016

Objective

Examine relationships between parental mealtime strategies used in the family meal session of family‐based treatment (FBT) and adolescent outcomes at EOT (session 20).

Method

Eighteen families with an adolescent receiving FBT‐AN participated. Parental strategies during videoed family meals were assessed using a family mealtime coding system. Change scores were calculated for both adolescent %EBW and EDE scores.

Results

Increased use of parental direct and non‐direct eating prompts during the family meal was associated with greater adolescent weight gain at EOT. Use of parental mealtime strategies was not associated with any significant change in adolescent eating psychopathology at EOT.

Discussion

Parental verbal eating prompts during the family meal may be effective in promoting short‐term weight gain. During the family meal session, parents should be encouraged to maintain a direct focus on their adolescent child's eating behaviour which may assist their child with food consumption and potential weight gain. Further research examining food‐based interactions among parents and their adolescent child with AN is needed. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2017; 50:433–436)
Biotic interactions mediate the influence of bird colonies on vegetation and soil chemistry at aggregation sites
Authors: Natusch Daniel James Deans , Lyons Jessica Ann , Brown Gregory P. , Shine Richard
Published: November 2016

Colonial‐nesting organisms can strongly alter the chemical and biotic conditions around their aggregation sites, with cascading impacts on other components of the ecosystem. In tropical Australia, Metallic Starlings (Aplonis metallica) nest in large colonies far above the forest canopy, in emergent trees. The ground beneath those trees is open, in stark contrast to the dense foliage all around. We surveyed the areas beneath 27 colony trees (and nearby randomly chosen trees lacking bird colonies) to quantify the birds' impacts on soil and vegetation characteristics, and to test alternative hypotheses about the proximate mechanisms responsible for the lack of live vegetation beneath colony trees. Nutrient levels were greatly elevated beneath colony trees (especially, those with larger colonies), potentially reaching levels toxic to older trees. However, seedlings thrived in the soil from beneath colony trees. The primary mechanism generating open areas beneath colony trees is disturbance by scavengers (feral pigs and native Turkeys) that are attracted in vast numbers to these nutrient hotspots. Seedlings flourished within exclosures inaccessible to vertebrate herbivores, but were rapidly consumed if unprotected. Our results contrast with previous studies of colonies of seabirds on remote islands, where a lack of large terrestrial herbivores results in bird colonies encouraging rather than eliminating vegetation in areas close to the nesting site. In our continental study system, scavengers may rapidly dilute the spatial heterogeneity generated by the massive nutrient subsidy from bird colonies.
Green Organocatalytic Dihydroxylation of Alkenes
Authors: Theodorou Alexis , Triandafillidi Ierasia , Kokotos Christoforos G.
Published: November 2016

An inexpensive, green, metal‐free one‐pot procedure for the dihydroxylation of alkenes is described. H2O2 and 2,2,2‐trifluoroacetophenone were employed as the oxidant and organocatalyst, respectively, in this highly sustainable protocol in which a variety of homoallylic alcohols, aminoalkenes, and simple alkenes were converted into the corresponding polyalcohols in good to excellent yields. This process takes advantage of an epoxidation reaction followed by an acidic treatment in which water participates in the ring opening of the in situ prepared epoxide to lead to the desired product.
BODIPY‐Based Profluorescent Probes Containing Meso‐ and β‐Substituted Isoindoline Nitroxides
Authors: Allen Jesse P. , Pfrunder Michael C. , McMurtrie John C. , Bottle Steven E. , Blinco James P. , Fairfull‐Smith Kathryn E.
Published: November 2016

BODIPY is a highly versatile fluorophore for biological imaging with a tunable fluorescence emission (500–800 nm) that overlaps the optically transparent window for tissue (600–1300 nm). Herein, we describe the synthesis of optically distinct BODIPY‐based profluorescent probes bearing meso‐ and β‐substituted isoindoline nitroxides and their corresponding methoxyamine derivatives. These profluorescent nitroxide probes possess strongly suppressed fluorescence, which can be revealed upon reduction or reaction with other radicals. Examination of the pentafluorophenylhydrazine reduction of the prepared probes by using tandem electron paramagnetic resonance (EPR) and fluorescence spectroscopy demonstrated that the asymmetric bis‐β‐substituted probe 9 (λem = 603 nm) was reduced the fastest; however, the greatest difference in fluorescence emission between the nitroxide and its reduced hydroxylamine analogue was observed for probe 7 (λem = 570 nm). The significant difference in fluorescence output between the nitroxides and their corresponding diamagnetic derivatives makes these probes ideal tools for imaging reactive oxygen species in biological systems.
Experimental and analytical study on the performance of particle tuned mass dampers under seismic excitation
Authors: Lu Zheng , Chen Xiaoyi , Zhang Dingchang , Dai Kaoshan
Published: November 2016

A particle tuned mass damper (PTMD), which is a creative integration of a traditional tuned mass damper and an efficient particle damper in the vibration control area, is proposed. This paper presents a comprehensive study that involves experimental, analytical, and computational approaches. The vibration control effects of a PTMD that is attached to a five‐story steel frame under seismic input are investigated by a series of shaking table tests. The influence of some parameters (auxiliary mass ratio, gap clearance, mass ratio of particles to the total auxiliary mass, frequency characteristics, and amplitude level of the input) is explored, and the performance of the PTMD with/without buffered material is compared. The experimental results show that the PTMD can achieve significant damping effects under seismic excitations, and the bandwidth of the suppression frequency is expanded, showing the device's robustness and control efficiency. In addition, an approximately analytical solution that is based on the concept of an equivalent single‐particle damper is presented, and the method to determine the corresponding system parameters is introduced. A comparative study between experimental and numerical results is conducted to verify the feasibility and accuracy of this analytical model. Copyright © 2016 John Wiley & Sons, Ltd.
Numerical simulation and seismic performance evaluation of buried pipelines rehabilitated with cured‐in‐place‐pipe liner under seismic wave propagation
Authors: Zhong Zilan , Filiatrault Andre , Aref Amjad
Published: November 2016

The cured‐in‐place‐pipe (CIPP) liner technology involves installation of flexible polymeric composite liners coated with thermosetting resin to the inner surfaces of existing buried pipelines. This innovative technology provides an efficient, economic, and environmentally friendly alternative for rehabilitation of structurally compromised underground pipelines without expensive and disruptive excavation. However, the lack of analytical/numerical procedures to quantify the seismic performance of CIPP liner reinforced pipelines remains a barrier to the seismic design and rehabilitation of underground pipelines. This paper first develops an experimentally validated hysteretic model of ductile iron push‐on joints, reinforced with one particular type of CIPP liner under repeated axial loading. A numerical procedure is then proposed to systematically assess the seismic performance and fragility of straight buried pipelines incorporating push‐on joints and subjected to transient ground deformations. The numerical results indicate that CIPP liner‐reinforced pipelines exhibit favorable robust seismic performance with limited joint damage under high‐intensity transient ground deformations. Copyright © 2016 John Wiley & Sons, Ltd.
Impacts of relative permeability hysteresis on the reservoir performance in CO2 storage in the Ordos Basin
Authors: Li Cai , Zhang Keni , Guo Chaobin , Xie Jian , Zhao Jing , Li Xia , Maggi Federico
Published: November 2016

The CO2 storage reservoir for the Shenhua Carbon Capture and Storage (SHCCS) Demonstration Project in the Ordos Basin in China is known for its low‐permeability and low‐porosity characteristics. However, injectivity was shown by the in situ monitoring data to be substantially increasing over the years. Previous numerical analyses suggest that such reservoir behavior might be mainly attributed to the permeability heterogeneity of the injection layers. As an intermittent injection procedure was actually practiced in this project, the hysteretic behaviors in relative permeability and capillary pressure in the reservoir could be significant. In this study, the hysteretic processes are investigated for a better understanding of the reservoir performance. History‐match is achieved with one order of magnitude lower in the overall permeability of the principal injection layer than the previous simulation. Current calibrated permeability is much closer to seismic measurement and well‐log results. Therefore, we believe that the hysteresis effects accompanying the alternation between injection and injection pause might be another important factor accounting for the observed reservoir performance. It is indicated in this study that, by considering the hysteresis effects in the injection‐pause sequence, an optimally‐designed intermittent injection procedure could greatly improve the injection performance in a saline aquifer with low permeability and low porosity that may seem unfavorable to CO2 storage. © 2016 Society of Chemical Industry and John Wiley & Sons, Ltd.
Deregulated neddylation in liver fibrosis
Authors: Zubiete‐Franco Imanol , Fernández‐Tussy Pablo , Barbier‐Torres Lucía , Simon Jorge , Fernández‐Ramos David , Lopitz‐Otsoa Fernando , Gutiérrez‐de Juan Virginia , de Davalillo Sergio López , Duce Antonio Martín , Iruzubieta Paula , Taibo Daniel , Crespo Javier , Caballeria Juan , Villa Erica , Aurrekoetxea Igor , Aspichueta Patricia , Varela‐Rey Marta , Lu Shelly C , Mato José M. , Beraza Naiara , Delgado Teresa C. , Martínez‐Chantar María L
Published: November 2016

Hepatic fibrosis is a global health problem currently without effective therapeutic approaches. Even though the ubiquitin‐like posttranslational modification of neddylation, that conjugates Nedd8 (neural precursor cell expressed developmentally downregulated) to specific targets, is aberrant in many pathologies, its relevance in liver fibrosis (LF) remained unexplored. Our results show deregulated neddylation in clinical fibrosis and both in mouse bileductligation– and CCl4‐induced fibrosis. Importantly, neddylation inhibition, by using the pharmacological inhibitor, MLN4924, reduced liver injury, apoptosis, inflammation, and fibrosis by targeting different hepatic cell types. On one hand, increased neddylation was associated with augmented caspase 3 activity in bile‐acid–induced apoptosis in mouse hepatocytes whereas neddylation inhibition ameliorated apoptosis through reduction of expression of the Cxcl1 and Ccl2 chemokines. On the other hand, chemokine receptors and cytokines, usually induced in activated macrophages, were reduced after neddylation inhibition in mouse Kupffer cells. Under these circumstances, decreased hepatocyte cell death and inflammation after neddylation inhibition could partly account for reduction of hepatic stellate cell (HSC) activation. We provide evidence that augmented neddylation characterizes activated HSCs, suggesting that neddylation inhibition could be important for resolving LF by directly targeting these fibrogenic cells. Indeed, neddylation inhibition in activated HSCs induces apoptosis in a process partly mediated by accumulation of c‐Jun, whose cullin‐mediated degradation is impaired under these circumstances. Conclusion: Neddylation inhibition reduces fibrosis, suggesting neddylation as a potential and attractive therapeutic target in liver fibrosis. (Hepatology 2017;65:694‐709).
Effect of statin on hepatocellular carcinoma in patients with type 2 diabetes: A nationwide nested case‐control study
Authors: Kim Gyuri , Jang Suk‐Yong , Han Eugene , Lee Yong‐ho , Park Se‐young , Nam Chung Mo , Kang Eun Seok
Published: November 2016

Relationship on new statin use and the risk of hepatocellular carcinoma (HCC) in patients with incident type 2 diabetes mellitus (T2DM), who might be at the risk of developing HCC, is uncertained. A nationwide population–based nested case–control study was conducted within the National Health Insurance Service National Sample Cohort 2002–2013 in Korea. Newly prescribed statin after newly diagnosed T2DM was defined as statin use. Controls were matched to case patients on age, sex, follow–up time, and the date of diabetes diagnosis at a five–to–one ratio. Odds ratios (ORs) for associations of statin use with HCC were calculated using conditional logistic regression. After at least a 5‐year HCC–free period, there were 229 incident HCC cases and 1,145 matched controls from 47,738 patients with incident diabetes. Of these 229 incident HCC cases, 27 (11.8%) were statin users, whereas 378 (33.0%) were statin users among 1,145 controls. Statin use was associated with a reduced risk of HCC development (adjusted OR [AOR]= 0.36, 95% confidence interval [CI] 0.22–0.60) after adjustment for chronic viral hepatitis, liver cirrhosis, alcoholic liver disease, previous cancer, aspirin use, insulin use, sulfonylurea use, metformin use, thiazolidinedione use, history of chronic obstructive pulmonary disease, Charlson comorbidity score, household income level, and residential area. Risk reduction was accentuated with an increase of cumulative defined daily doses (cDDD) compared with non–users (AORs 0.53, 0.36, 0.32, and 0.26 in ≤60, 60–180, 181–365, and >365cDDD, respectively; P for trend <0.0001). The risk reduction was apparent in the presence of liver disease (AOR = 0.27, 95% CI 0.14–0.50), including heterogeneous groups of clinical diagnosis of liver disease, but not significant in the absence of liver disease (AOR = 0.64, 95% CI 0.32–1.29). Among patients with new onset T2DM, statin use before HCC diagnosis may have a beneficial inhibitory effect on HCC development in a dose–dependent manner, especially in individuals with liver disease.
Sexual divergence in activity‐dependent neuroprotective protein impacting autism, schizophrenia, and Alzheimer's disease
Authors: Gozes Illana
Published: November 2016

Discovered in our laboratory, activity‐dependent neuroprotective protein (ADNP) interacts with key regulatory proteins, including the chromatin remodeling complex SWI/SNF, proteins associated with RNA splicing, RNA translation, microtubule dynamics, and autophagy. ADNP regulates > 400 genes during mouse embryonic development and is essential for neural tube closure. ADNP key functions extend from mice to men, with mutations causing ADNP‐related ID/autism syndrome, also known as the Helsmoortel‐Van der Aa syndrome. ADNP mRNA increases in lymphocytes derived from schizophrenia patients and in patients suffering from mild cognitive impairment (MCI) and further increases in Alzheimer's disease patients compared with controls. Serum ADNP levels correlate with IQ. NAP (davunetide), an ADNP snippet drug candidate, protects cognition in patients suffering from amnestic MCI preceding Alzheimer's disease and significantly enhances functional daily activities in schizophrenia patients toward future development. It is important to note that ADNP is sexually regulated in the brains of birds, mice, and men and in lymphocytes of patients suffering from schizophrenia. ADNP haploinsufficiency in mice results in significantly decreased axonal transport (with male–female differences) changes in gene expression in a sex‐dependent manner, including key regulatory mechanisms during brain and heart development and function and behavioral outcomes. These findings pave the path for better understanding of brain function through the prism of sex differences. © 2016 Wiley Periodicals, Inc.
The immune system as a novel regulator of sex differences in brain and behavioral development
Authors: Nelson Lars H. , Lenz Kathryn M.
Published: November 2016

Sexual differentiation of the brain occurs early in life as a result of sex‐typical hormone action and sex chromosome effects. Immunocompetent cells are being recognized as underappreciated regulators of sex differences in brain and behavioral development, including microglia, astrocytes, and possibly other less well studied cell types, including T cells and mast cells. Immunocompetent cells in the brain are responsive to steroid hormones, but their role in sex‐specific brain development is an emerging field of interest. This Review presents a summary of what is currently known about sex differences in the number, morphology, and signaling profile of immune cells in the developing brain and their role in the early‐life programming of sex differences in brain and behavior. We review what is currently known about sex differences in the response to early‐life perturbations, including stress, inflammation, diet, and environmental pollutants. We also discuss how and why understanding sex differences in the developing neuroimmune environment may provide insight into understanding the etiology of several neurodevelopmental disorders. This Review also highlights what remains to be discovered in this emerging field of developmental neuroimmunology and underscores the importance of filling in these knowledge gaps. © 2016 Wiley Periodicals, Inc.
Estradiol shifts interactions between the infralimbic cortex and central amygdala to enhance fear extinction memory in female rats
Authors: Maeng Lisa Y. , Cover Kara K. , Taha Mohamad B. , Landau Aaron J. , Milad Mohammed R. , Lebrón‐Milad Kelimer
Published: November 2016

There is growing evidence that estradiol (E2) enhances fear extinction memory consolidation. However, it is unclear how E2 influences the nodes of the fear extinction network to enhance extinction memory. This study begins to delineate the neural circuits underlying the influence of E2 on fear extinction acquisition and consolidation in female rats. After fear conditioning (day 1), naturally cycling female rats underwent extinction learning (day 2) in a low‐E2 state, receiving a systemic administration of either E2 or vehicle prior to extinction training. Extinction memory recall was then tested 24 hr later (day 3). We measured immediate early gene c‐fos expression within the extinction network during fear extinction learning and extinction recall. During extinction learning, E2 treatment increased centrolateral amygdala c‐fos activity and reduced lateral amygdala activity relative to vehicle. During extinction recall, E2‐treated rats exhibited reduced c‐fos expression in the centromedial amygdala. There were no group differences in c‐fos expression within the medial prefrontal cortex or dorsal hippocampus. Examining c‐fos ratios with the infralimbic cortex (IL) revealed that, despite the lack of group differences within the IL, E2 treatment induced greater IL activity relative to both prelimbic cortex and central amygdala (CeA) activity during extinction memory recall. Only the relationship between IL and CeA activity positively correlated with extinction retention. In conclusion, E2 appears to modify interactions between the IL and the CeA in females, shifting from stronger amygdalar modulation of fear during extinction learning to stronger IL control during extinction recall. © 2016 Wiley Periodicals, Inc.
Sex differences in the functional lateralization of emotion and decision making in the human brain
Authors: Reber Justin , Tranel Daniel
Published: November 2016

Dating back to the case of Phineas Gage, decades of neuropsychological research have shown that the ventromedial prefrontal cortex (vmPFC) is crucial to both real‐world social functioning and abstract decision making in the laboratory (see, e.g., Stuss et al., ; Bechara et al., 1994; Damasio et al., ). Previous research has shown that the relationship between the laterality of individuals' vmPFC lesions and neuropsychological performance is moderated by their sex, whereby there are more severe social, emotional, and decision‐making impairments in men with right‐side vmPFC lesions and in women with left‐side vmPFC lesions (Tranel et al., 2005; Sutterer et al., 2015). We conducted a selective review of studies examining the effect of vmPFC lesions on emotion and decision making and found further evidence of sex‐related differences in the lateralization of function not only in the vmPFC but also in other neurological structures associated with decision making and emotion. This Mini‐Review suggests that both sex and laterality effects warrant more careful consideration in the scientific literature. © 2016 Wiley Periodicals, Inc.
Sex and stress: Men and women show different cortisol responses to psychological stress induced by the Trier social stress test and the Iowa singing social stress test
Authors: Reschke‐Hernández Alaine E. , Okerstrom Katrina L. , Bowles Edwards Angela , Tranel Daniel
Published: November 2016

Acute psychological stress affects each of us in our daily lives and is increasingly a topic of discussion for its role in mental illness, aging, cognition, and overall health. A better understanding of how such stress affects the body and mind could contribute to the development of more effective clinical interventions and prevention practices. Over the past 3 decades, the Trier Social Stress Test (TSST) has been widely used to induce acute stress in a laboratory setting based on the principles of social evaluative threat, namely, a judged speech‐making task. A comparable alternative task may expand options for examining acute stress in a controlled laboratory setting. This study uses a within‐subjects design to examine healthy adult participants' (n = 20 men, n = 20 women) subjective stress and salivary cortisol responses to the standard TSST (involving public speaking and math) and the newly created Iowa Singing Social Stress Test (I‐SSST). The I‐SSST is similar to the TSST but with a new twist: public singing. Results indicated that men and women reported similarly high levels of subjective stress in response to both tasks. However, men and women demonstrated different cortisol responses; men showed a robust response to both tasks, and women displayed a lesser response. These findings are in line with previous literature and further underscore the importance of examining possible sex differences throughout various phases of research, including design, analysis, and interpretation of results. Furthermore, this nascent examination of the I‐SSST suggests a possible alternative for inducing stress in the laboratory. © 2016 Wiley Periodicals, Inc.
Sex differences in innate immunity and its impact on opioid pharmacology
Authors: Doyle Hillary H. , Murphy Anne Z.
Published: November 2016

Morphine has been and continues to be one of the most potent and widely used drugs for the treatment of pain. Clinical and animal models investigating sex differences in pain and analgesia demonstrate that morphine is a more potent analgesic in males than in females. In addition to binding to the neuronal μ‐opioid receptor, morphine binds to the innate immune receptor toll‐like receptor 4 (TLR4), located on glial cells. Activation of glial TLR4 initiates a neuroinflammatory response that directly opposes morphine analgesia. Females of many species have a more active immune system than males; however, few studies have investigated glial cells as a potential mechanism driving sexually dimorphic responses to morphine. This Mini‐Review illustrates the involvement of glial cells in key processes underlying observed sex differences in morphine analgesia and suggests that targeting glia may improve current treatment strategies for pain. © 2016 Wiley Periodicals, Inc.
Sex differences in stroke therapies
Authors: Sohrabji Farida , Park Min Jung , Mahnke Amanda H.
Published: November 2016

Stroke is the fifth leading cause of death and acquired disability in aged populations. Women are disproportionally affected by stroke, having a higher incidence and worse outcomes than men. Numerous preclinical studies have discovered novel therapies for the treatment of stroke, but almost all of these have been shown to be unsuccessful in clinical trials. Despite known sex differences in occurrence and severity of stroke, few preclinical or clinical therapeutics take into account possible sex differences in treatment. Reanalysis of data from studies of tissue plasminogen activator (tPA), the only currently FDA‐approved stroke therapy, has shown that tPA improves stroke outcomes for both sexes and also shows sexual dimorphism by more robust improvement in stroke outcome in females. Experimental evidence supports the inclusion of sex as a variable in the study of a number of novel stroke drugs and therapies, including preclinical studies of anti‐inflammatory drugs (minocycline), stimulators of cell survival (insulin‐like growth factor‐1), and inhibitors of cell death pathways (pharmacological inhibition of poly[ADP‐ribose] polymerase‐1, nitric oxide production, and caspase activation) as well as in current clinical trials of stem cell therapy and cortical stimulation. Overall, study design and analysis in clinical trials as well as in preclinical studies must include both sexes equally, consider possible sex differences in the analyses, and report the differences/similarities in more systematic/structured ways to allow promising therapies for both sexes and increase stroke recovery. © 2016 Wiley Periodicals, Inc.
Sex‐based differences in brain alterations across chronic pain conditions
Authors: Gupta Arpana , Mayer Emeran A. , Fling Connor , Labus Jennifer S. , Naliboff Bruce D. , Hong Jui‐Yang , Kilpatrick Lisa A.
Published: November 2016

Common brain mechanisms are thought to play a significant role across a multitude of chronic pain syndromes. In addition, there is strong evidence for the existence of sex differences in the prevalence of chronic pain and in the neurobiology of pain. Thus, it is important to consider sex when developing general principals of pain neurobiology. The goal of the current Mini‐Review is to evaluate what is known about sex‐specific brain alterations across multiple chronic pain populations. A total of 15 sex difference and 143 single‐sex articles were identified from among 412 chronic pain neuroimaging articles. Results from sex difference studies indicate more prominent primary sensorimotor structural and functional alterations in female chronic pain patients compared with male chronic pain patients: differences in the nature and degree of insula alterations, with greater insula reactivity in male patients; differences in the degree of anterior cingulate structural alterations; and differences in emotional‐arousal reactivity. Qualitative comparisons of male‐specific and female‐specific studies appear to be consistent with the results from sex difference studies. Given these differences, mixed‐sex studies of chronic pain risk creating biased data or missing important information and single‐sex studies have limited generalizability. The advent of large‐scale neuroimaging databases will likely aid in building a more comprehensive understanding of sex differences and commonalities in brain mechanisms underlying chronic pain. © 2016 Wiley Periodicals, Inc.
Sex differences modulating serotonergic polymorphisms implicated in the mechanistic pathways of risk for depression and related disorders:
Authors: Perry LeeAnn M. , Goldstein‐Piekarski Andrea N. , Williams Leanne M.
Published: November 2016

Despite consistent observations of sex differences in depression and related emotional disorders, we do not yet know how these sex differences modulate the effects of genetic polymorphisms implicated in risk for these disorders. This Mini‐Review focuses on genetic polymorphisms of the serotonergic system to illustrate how sex differences might modulate the neurobiological pathways involved in the development of depression. We consider the interacting role of environmental factors such as early‐life stress. Given limited current knowledge about this topic, we highlight methodological considerations, challenges, and guidelines for future research. © 2016 Wiley Periodicals, Inc.
Cortisol reactivity and emotional memory after psychosocial stress in oral contraceptive users
Authors: Mordecai Kristen L. , Rubin Leah H. , Eatough Erin , Sundermann Erin , Drogos Lauren , Savarese Antonia , Maki Pauline M.
Published: November 2016

Oral contraceptive (OC) users typically show a blunted or no cortisol response to psychosocial stress. Although most OC regimens include both an inactive (dummy) and active pill phase, studies have not systematically investigated cortisol responses during these pill phases. Further, high levels of cortisol following a stressor diminish retrieval of emotional material, but the effects of stress on memory among OC users are poorly understood. We examined the effects of a psychosocial stressor, the Trier Social Stress Test, vs. a control condition on cortisol responsivity and emotional memory retrieval in women tested either during their active (n = 18) or inactive pill phase (n = 21). In secondary analyses, we quantitatively compared OC users with normally cycling women and showed a significant lack of cortisol response during both active and inactive pill phase. Emotional recall did not differ between active and inactive pill phases. Stress differentially diminished recall of negative words compared with positive or neutral words, but cortisol levels were unrelated to memory performance. These findings indicate that OC users have distinct cortisol and memory responses to stress that are similar between the active and inactive pill phases. © 2016 Wiley Periodicals, Inc.
Sexual modulation of sex‐shared neurons and circuits in Caenorhabditis elegans
Authors: Portman Douglas S.
Published: November 2016

Studies using the nematode C. elegans have provided unique insights into the development and function of sex differences in the nervous system. Enabled by the relative simplicity of this species, comprehensive studies have solved the complete cellular neuroanatomy of both sexes as well as the complete neural connectomes of the entire adult hermaphrodite and the adult male tail. This work, together with detailed behavioral studies, has revealed three aspects of sex differences in the nervous system: sex‐specific neurons and circuits; circuits with sexually dimorphic synaptic connectivity; and sex differences in the physiology and functions of shared neurons and circuits. At all of these levels, biological sex influences neural development and function through the activity of a well‐defined genetic hierarchy that acts throughout the body to translate chromosomal sex into the state of a master autosomal regulator of sexual differentiation, the transcription factor TRA‐1A. This Review focuses on the role of genetic sex in implementing sex differences in shared neurons and circuits, with an emphasis on linking the sexual modulation of specific neural properties to the specification and optimization of sexually divergent and dimorphic behaviors. An important and unexpected finding from these studies is that chemosensory neurons are a primary focus of sexual modulation, with genetic sex adaptively shaping chemosensory repertoire to guide behavioral choice. Importantly, hormone‐independent functions of genetic sex are the principal drivers of all of these sex differences, making nematodes an excellent model for understanding similar but poorly understood mechanisms that likely act throughout the animal kingdom. © 2016 Wiley Periodicals, Inc.
(Putative) sex differences in neuroimmune modulation of memory
Authors: Tronson Natalie C. , Collette Katie M.
Published: November 2016

The neuroimmune system is significantly sexually dimorphic, with sex differences evident in the number and activation states of microglia, in the activation of astrocytes, and in cytokine release and function. Neuroimmune cells and signaling are now recognized as critical for many neural functions throughout the life span, including synaptic plasticity and memory function. Here we address the question of how cytokines, astrocytes, and microglia contribute to memory, and specifically how neuroimmune modulation of memory differentially affects males and females. Understanding sex differences in both normal memory processes and dysregulation of memory in psychiatric and neurological disorders is critical for developing treatment and preventive strategies for memory disorders that are effective for both men and women. © 2016 Wiley Periodicals, Inc.