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In the course of the nineteenth century, Russia’s press culture underwent a dramatic cultural, technological, and political transformation. However, the question of professionalization of the press during the same period remains relatively underexplored. This article examines the extent and the limitations of editorial professionalization in nineteenth-century Russia by focusing on an emergent generation of private newspaper editors such as M.N. Katkov, A.A. Kraevskii, I.S. Aksakov, and A.S. Suvorin during the 1860s and 1870s. The article explores the emergence of a private opinion press during the 1860s with substantial autonomy in the commercial management of their newspapers, but a censorship-restricted autonomy in the management of their content. It then examines the elements of an emerging professional ethos and solidarity in the editorial profession. Drawing on a wealth of correspondence, editorials, and diaries, this work reveals the delicate world of personal relationships which allowed editors to balance both the strictures of political censorship and the account books of their commercial enterprises. This paper argues that a limited professional autonomy and considerable competition among influential editors – i.e press lords – constrained the professionalization of the journalism in pre-Revolutionary Russia.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The LOOP Study was funded by Innovation Fund Denmark [grant number 12-1352259], The Research Foundation for the Capital Region of Denmark, The Danish Heart Foundation [grant number 11-04-R83-A3363-22625], Aalborg University Talent Management Program, Arvid Nilssons Fond, Skibsreder Per Henriksen, R og Hustrus Fond, the European Union’s Horizon 2020 program [grant number 847770], Læge Sophus Carl Emil Friis og hustru Olga Doris Friis’ Legat, and an unrestricted grant from Medtronic. Background It is well known that atrial fibrillation (AF) confers a substantially increased risk of ischemic stroke, but data on health benefits from AF screening are scarce. The newly proposed MVP risk score combining the duration, voltage and morphology of P-wave has been demonstrated to be predictive of AF and might therefore also be useful in risk-stratifying individuals for AF screening and subsequent treatment. Purpose The present study sought to examine MVP risk score and its P-wave components for prediction of AF screening effects. Methods The LOOP Study randomized AF-naïve individuals aged 70-90 years with additional stroke risk factors to either continuous AF screening with implantable loop recorder (ILR) and subsequent anticoagulation initiation upon detection of AF episode ≥6 minutes, or usual care. In this secondary analysis, the LOOP participants with a baseline 12-lead electrocardiogram (ECG) suitable for P-wave measurement were included. Results Of 5759 participants included, 265 (4.6%) had had ischemic stroke during follow-up: 213 (4.9%) of 4311 in the control group versus 64 (3.6%) of 1448 in the ILR group. Among the participants in the control group, a significantly increased risk of ischemic stroke was observed for MVP score 5-6 versus score 0-2 (hazard ratio (HR) 1.66 [95% confidence interval (CI): 1.01-2.75]) and for the presence of interatrial block (IAB) versus no IAB (HR 1.85 [95% CI: 1.19-2.86]), whereas a P-wave voltage in lead I (PWVI) 110 versus ≤110 ms). Compared with usual care, ILR screening did not significantly reduce the stroke risk regardless of MVP risk score, PWD, PWVI, or IAB pattern at baseline. Conclusions In an elderly population with additional stroke risk factors, both the P-wave parameters and the combined MVP risk score based on 12-lead ECG were associated with ischemic stroke, but these did not successfully demonstrate an association with effects of AF screening on stroke prevention.

Background Previous research has showed that various cardiovascular diseases (CVD) are associated with increased risks of atrial fibrillation (AF) and stroke. However, data on the interaction between CVD and AF screening efficacy are lacking. Purpose To evaluate the influence of preexisting CVD on the effects of AF screening with long-term continuous monitoring. Methods The LOOP Study (Atrial Fibrillation detected by Continuous ECG Monitoring using Implantable Loop Recorder to prevent Stroke in High-risk Individuals) randomized AF-naïve individuals aged ≥70 years and with additional stroke risk factors to either long-term screening with implantable loop recorder (ILR) and subsequent anticoagulation initiation upon detection of AF episodes ≥6 minutes, or usual care (the control group). In the current study, all participants from the LOOP Study were divided into two risk groups according to the presence of CVD (defined as ischemic heart disease, heart failure, previous stroke, valvular heart disease, or peripheral artery disease). The relative risks of outcomes in groupwise comparisons, as indicated by hazard ratio (HR), were assessed in the cause-specific Cox proportional-hazards model with death as competing risk. Results Of 6004 participants included, 1997 (33.3%) had ≥1 CVD at baseline. Compared with no CVD, the presence of CVD was associated with increased risks of AF diagnosis in the ILR group (adjusted HR 1.32 [1.09–1.59]) and of stroke or systemic arterial embolism in the entire study cohort (adjusted HR 1.34 [1.06–1.69]). For ILR screening versus usual care, there was no decrease in stroke or systemic arterial embolism among participants with preexisting CVD (adjusted HR 1.13 [0.76–1.68]), whereas a significant risk reduction was obtained by screening among those without CVD (adjusted HR 0.64 [0.44–0.93]). The interaction was significant (adjusted p-value for interaction 0.041). Conclusions In an elderly, high-risk population, ILR screening did not prevent stroke significantly in individuals with preexisting CVD, but it was associated with an approximately 40% risk reduction among those without CVD. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The LOOP Study was funded by Innovation Fund Denmark [grant number 12-1352259], The Research Foundation for the Capital Region of Denmark, The Danish Heart Foundation [grant number 11-04-R83-A3363-22625], Aalborg University Talent Management Program, Arvid Nilssons Fond, Skibsreder Per Henriksen, R og Hustrus Fond, the European Union's Horizon 2020 program [grant number 847770], Læge Sophus Carl Emil Friis og hustru Olga Doris Friis' Legat, and an unrestricted grant from Medtronic.

Pancreatic ductal adenocarcinoma (PDA) is the 4th leading cause of cancer death in the U.S. with only about a 10% five-year survival rate and an estimated 60,000 deaths/year by 2030. Poor survival is frequently due to advanced disease at the time of diagnosis, as well as the high prevalence of KRAS driver mutations. Currently, approved KRAS-targeted therapeutics are designed to covalently inactivate only KRAS-G12C mutants, whereas the most common mutations in PDA are KRAS-G12D, KRAS-G12V, and KRAS-G12R. Thus, the need for novel RAS-targeted therapeutics with efficacy in tumors with these more common mutations is of utmost urgency to reduce PDA disease burden. We have synthesized a novel chemical class of pan-RAS inhibitors with unique biological properties and attractive drug-like properties. As a prodrug, ADT-1004, generates an active metabolite, ADT-007, that potently inhibits the growth of human and murine PDA cell lines in vitro with single-digit nM IC50 irrespective of specific RAS mutational codon or isozyme by inhibiting activated RAS and signaling downstream of KRAS (ERK1/2 and AKT phosphorylation). ADT-1004 is well tolerated with no discernable toxicity at oral dosages of up to 175 mg/kg bid. Pharmacokinetic studies demonstrated that ADT-1004 produces sustained plasma concentrations of ADT-007 ~50-fold above IC50 values, with even higher concentrations in both subcutaneous and orthotopic pancreatic tumors. Once daily oral administration of ADT-1004 significantly inhibited the growth of orthotopically implanted PDA tumors with a corresponding reduction in RAS/MAPK signaling. ADT-1004 represents a 1st-in-class pan-RAS inhibitor with potential advantages over mutant-specific KRAS inhibitors for greater efficacy and ability to avert mechanisms of resistance. These data support future clinical trials of ADT-1004 as a monotherapy for the treatment of patients with PDA regardless of the underlying mutation. Citation Format: Yulia Y. Maxuitenko, Jeremy B. Foote, Adam B. Keeton, Xi Chen, Kristy Berry, Khalda Fadlalla, Jacob Valiyaveettil, Chung-Hui Huang, Austin M. Moore, Emily C. Graff, Ganji P. Nagaraju, Julienne L. Carstens, Bassel F. El-Rayes, Donald J. Buchsbaum, Gary A. Piazza. Antitumor activity of 1st-in-class pan-RAS inhibitor ADT-1004 in mouse models of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB322.

Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Svend Andersens Foundation Karl G Andersens Foundation Helsefonden Background Right ventricular (RV) pacing may induce electrical and mechanical dyssynchrony which may lead to heart failure. Often, the physician aims for lead implantation at the RV septum as this is expected to result in a more physiologic activation compared to alternative RV lead locations. Fluoroscopy, often in combination with QRS morphology derived from the 12-lead ECG, is used to guide lead implantation. However, this method is inaccurate and can result in a non-optimal RV lead location. We present a novel non-invasive method to create patient-specific 3D electrical activation maps from the 12-lead ECG that has potential to support RV lead implantation. Methods Data from 34 patients with an implanted dual chamber pacemaker were used. A contrast-enhanced cardiac CT scan showing the RV lead implantation site was obtained as well as recording of a 12-lead ECG during RV pacing together with a 3D photo documenting the ECG electrode positions. Discrete patient-specific torso and heart models were created from the CT scans. Each torso model was merged with the 3D photo for precise placement of the ECG electrodes in relation to the heart (figure 1). Combining the 12-lead ECGs and the heart/torso models, patient-specific 3D electrical activation maps originating from the RV were created using a novel inverse-ECG technique applying electrophysiological rules. The accuracy of the inverse-ECG method was determined by comparing the earliest site of activation from the 3D activation map with the known RV insertion site marked on the CT scan. Results Documented by the implanting physician in the medical records, 33 RV leads were estimated to be septal and one apical. Estimated from the CT scan 9 leads were placed septal, 18 apical and 7 on the free wall. The mean geodesic distance between the initial site of activation in the 3D activation map and the marked RV insertion site from CT was 13.6 ±5.7 mm (range 4.3-28.6). The distance for each patient is shown in figure 2. The initial site of activation was constrained to the discrete nodes of the ventricular model whereas the marker for RV lead position was localized freely on the CT scan. The average distance from the RV CT marker to the nearest discrete node was 4.3 ±2.2 mm. Correcting for this error, the geodesic distance between the initial site of activation and RV CT marker was 9.3 ±5.4 mm (range 0.0-24.6). The average time used for 3D activation map computation was 1.1 ±0.4 s per ECG. Conclusions We demonstrated a novel non-invasive 12-lead ECG-based method to accurately and effectively localize the RV lead in relation to the ventricular anatomy during RV pacing. Furthermore, we confirmed that the RV lead was often implanted in an unintended position. With further advancements, this method has the potential to support physicians during pacemaker implantation to ensure optimal RV lead positioning. Further studies are needed to confirm the accuracy.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The study was supported by The Innovation Fund Denmark [12-135225], The Research Foundation for the Capital Region of Denmark [no grant number], The Danish Heart Foundation [11-04-R83-A3363-22625], Aalborg University Talent Management Programme [no grant number], Arvid Nilssons Fond [no grant number], Skibsreder Per Henriksen, R. og Hustrus Fond [no grant number], Medtronic [no grant number], and the AFFECT-EU consortium which has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 847770. Background The interest in heart rhythm monitoring and technologies to detect arrhythmia is increasing. The prevalence and prognostic significance of subclinical bradyarrhythmias is unknown. Objectives To assess the accidental diagnosis of bradyarrhythmia and its subsequent treatment and prognostic impact in persons screened for atrial fibrillation compared to unscreened persons. Methods We utilized a randomized trial of ≥70-year-olds with cardiovascular risk factors recruited outside the hospital setting to receive implantable loop recorder screening for atrial fibrillation (ILR group) vs. usual care (Control group). Time-to-event analyses were performed for bradyarrhythmia, pacemaker implantation, syncope, and sudden cardiovascular death. Results A total of 6004 participants were randomized (mean age 75 years, 47% women, 91% with hypertension, 20% with prior syncope), 4503 to Control and 1501 to ILR. The median follow-up period was 64.5 [59.3, 69.8] months. A total of 675 deaths occurred with an overall rate of 2.16 (2.00-2.33) per 100 person-years, and 67 sudden cardiovascular deaths occurred with a rate of 0.21 (0.15-0.28) for the Control group and 0.23 (0.14-0.37) for the ILR group (hazard ratio (HR) 1.11 (0.64-1.90), p=0.71)). The overall rate of incident bradyarrhythmia was 1.63 (1.49-1.79) per 100 person-years, and bradyarrhythmia was diagnosed in 172 (3.82%) and 312 (20.8%) participants in the Control and ILR group, respectively (HR 6.21 (5.15-7.48), p Overall, a pacemaker was implanted in 132 (2.93%) and 66 (4.40%) participants (HR 1.53 (1.14-2.06), p Conclusions Bradyarrhythmias are highly common in ≥70-year-olds with cardiovascular risk factors. Compared to Control, ILR monitoring led to a six-fold increase in diagnosis of bradyarrhythmia and a significant increase in pacemaker implantations, but no change in the risk of syncope or sudden death.

Nonalcoholic fatty liver disease (NAFLD), which ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), is the most common chronic liver disease. Yet, the molecular mechanisms for the progression of steatosis to NASH remain largely undiscovered. Thus, there is a need for identifying specific gene and pathway changes that drive the progression of NAFLD. This study uses high-fat Western diet (HFWD) together with liquid sugar [fructose and sucrose (F/S)] feeding for 12 weeks in mice to induce obesity and examine hepatic transcriptomic changes that occur in NAFLD progression. The combination of a HFWD+F/S in the drinking water exacerbated HFWD-induced obesity, hyperinsulinemia, hyperglycemia, hepatic steatosis, inflammation, and human and murine fibrosis gene set enrichment that is consistent with progression to NASH. RNAseq analysis revealed differentially expressed genes (DEGs) associated with HFWD and HFWD+F/S dietary treatments compared to Chow-fed mice. However, liquid sugar consumption resulted in a unique set of hepatic DEGs in HFWD+F/S-fed mice, which were enriched in the complement and coagulation cascades using network and biological analysis. Cluster analysis identified Orosomucoid (ORM) as a HFWD+F/S upregulated complement and coagulation cascades gene that was also upregulated in hepatocytes treated with TNFα or free fatty acids in combination with hypoxia. ORM expression was found to correlate with NAFLD parameters in obese mice. Taken together, this study examined key genes, biological processes, and pathway changes in the liver of HFWD+F/S mice in an effort to provide insight into the molecular basis for which the addition of liquid sugar promotes the progression of NAFLD.

Objective: In light of COVID-19, leaders issued stay-at-home orders, including closure of higher-education schools. Most students left campus, likely impacting their employment and social network. Leaders are making decisions about opening universities and modality of instruction. Understanding students' psychological, physiological, academic, and financial responses to the shut-down and reopening of campuses can help leaders make informed decisions. Participants: 654 students from a large western university enrolled during the pandemic shutdown. Methods: Students were invited via email to complete an online survey. Results: Students reported stress, depression, loneliness, lack of motivation, difficulty focusing on schoolwork, restless sleep, appetite changes, job loss concerns, and difficulties coping. Most wanted to return to campus and felt social/physical distancing was effective but were mixed in terms of testing or masks. Conclusions: Moving to remote learning created physical and psychological stress. Students want to return to campus but do not want to take risk-reducing measures.

Students currently in and returning to college are increasingly likely to have children. The demands of academic and family life can conflict, making it difficult for student-parents to navigate bo...

Objective: Marriage is consistently associated with better health outcomes. Spouses' attempts to influence partners' lifestyle and general health behaviors may contribute to this effect, although partners may not be aware of this influence. Spousal worry of a cancer diagnosis for an at-risk partner may factor into attempts to influence. An examination of spousal worry and influence on lifestyle choices, general health behaviors, and cancer screening adherence for partners at higher risk of colorectal cancer may shed light on spousal influence and partners' perceptions of influence. Methods: A mixed-method design assessed cancer worry and spousal influence for risk-reducing behavior in first-degree relatives of colorectal cancer patients following personalized genetic counseling. Couples discussed current and future ways to reduce risk. Results: Both the at-risk partner and the spouses had moderately high cancer worries. Spouses reported exerting influence for healthier behavior and cancer screening adherence but at-risk partners did not always recognize it. Qualitative data demonstrated partners' perceptions of spousal influence toward better health decisions, and against better health decisions. Conclusions: Future research should examine how and when spouses choose to exert influence, type of influence, what strategies they use, and to what effect.

Aim: To provide a brief review of health concerns associated with a sedentary lifestyle and summarize some of the benefits of walking, with specific focus on the value of dog-walking programs as a means to improve health and wellness for the student nurse.Methods: A professor within the School of Nursing and Doctor of Veterinary Medicine collaborated to review research on the benefits of dog walking and interventions utilizing dogs to increase and sustain physical activity in their owners and those that enjoy the companionship a dog can provide.Results: Dog walking is an intervention to increase activity among student nurses due to companionship and the sense of obligation dogs provide. Research suggests that dog owners are more physically active with subsequent health benefits for both owners and dogs. Animal assisted therapy programs within the university setting can link students with dogs to improve physical activity.Conclusion: Dog walking has benefits to both people and dogs. Nursing faculty can develop physical activity programs within their institution that incorporate walking a dog to enhance physical activity among student nurses. Further research is needed to empirically evaluate effectiveness of dog walking in the student nurse population.

This study examined the role of relationship quality on physical and psychological health among older adults. It included 2,298 adults aged 50 and older who participated in the Midlife in the US national longitudinal study of health and well-being. We assessed the effect of spousal support and strain on psychological and physical health, controlling for age, education, income, depression levels and prior health. Results indicated that spousal support and strain affected psychological health but not physical health. Despite prior research showing an association between marital quality and physical health, this study did not support the conceptualization that relationship quality measured by spousal support or strain has a direct effect on long-term health in this sample of older adults. This study does not preclude the presence of a mediated or moderated association between relationship quality and physical health. Higher levels of spousal support are associated with positive psychological health among adults over age 50 while spousal strain is associated with negative psychological health. This study supports the premise that relationship quality has an ongoing impact on the psychological health of mature adults, bolstering arguments to include psychological health screening and couples relationship education among health services provided to older adults.

Being satisfied in marriage provides protective stress buffering benefits to various health complications but the causal mechanisms and speed at which this is accomplished is less well understood. Much of the research on health and marriage has conceptualized marital quality in a unidimensional way, with high levels of either positivity or negativity. This conceptualization may not fully capture the nuanced benefits of marital relationships. Pupillometry is an innovative method which captures the effects of marital stress buffering on the body’s autonomic nervous system in real time; pupil dilation occurs within 200ms to stress exposure. Additionally, this method records hundreds of readings per second, providing precision and sensitivity. This preregistered experiment aimed to conceptually replicate previous pupillometry stress buffering results and extend the previous findings by including a generalizable, real-life stressor—viewing a horror movie—and multidimensional relationship quality effects. Eighty-three couples (166 participants) were quasi-grouped, based on a self-reported multidimensional relationship quality scale, to either supportive or ambivalent marital relationship conditions. They were then randomly assigned to either a spousal support (i.e., handholding) or non-support (spousal absence) condition and watched clips from both horror and nature movies while pupil dilation was measured. Tonic pupillary response results revealed that the horror video clips elicited a stress response and there were significant differences between the support and non-support conditions, as well as marital relationship quality conditions. These results frame the precision, speed, and sensitivity of pupillometry as a potentially fruitful method to investigate the causal mechanisms linking stress buffering and supportive marital relationships.

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).

The distinction between biological processes of adipose tissue expansion is crucial to understanding metabolic derangements, but a robust method for quantifying adipocyte size has yet to be standardized. Here, we compared three methods for histological analysis in situ: one conventional approach using individual micrographs acquired by digital camera, and two with whole-slide image analysis pipelines involving proprietary (Visiopharm) and open-source software (QuPath with a novel ImageJ plugin). We found that micrograph analysis identified 10–40 times fewer adipocytes than whole-slide methods, and this small sample size resulted in high variances that could lead to statistical errors. The agreement of the micrograph method to measure adipocyte area with each of the two whole-slide methods was substantially less (R2 of 0.6644 and 0.7125) than between the two whole-slide methods (R2 of 0.9402). These inconsistencies were more pronounced in samples from high-fat diet fed mice. While the use of proprietary software resulted in the highest adipocyte count, the lower cost, ease of use, and minimal variances of the open-source software provided a distinct advantage for measuring the number and size of adipocytes. In conclusion, we recommend whole-slide image analysis methods to consistently measure adipocyte area and avoid unintentional errors due to small sample sizes.

Obesity is an immunometabolic disease associated with chronic inflammation and the dysregulation of pro- and anti-inflammatory cytokines. One hallmark of obesity is reduced concentrations of the anti-inflammatory adipokine, adiponectin. Pharmacologic doses of niacin produce multiple metabolic benefits, including attenuating high-fat diet (HFD)-induced adipose tissue inflammation and increasing adiponectin concentrations. To determine if adiponectin mediates the anti-inflammatory effects of niacin, male C57BL/6J (WT) and adiponectin null (Adipoq-/-) mice were maintained on a low-fat diet (LFD) or HFD for 6 weeks, before being administered either vehicle or niacin (360 mg/kg/day) for 5 weeks. HFD-fed mice had increased expression of genes associated with macrophage recruitment (Ccl2) and number (Cd68), and increased crown-like structure (CLS) number in adipose tissue. While niacin attenuated Ccl2 expression, there were no effects on Cd68 or CLS number. The absence of adiponectin did not hinder the ability of niacin to reduce Ccl2 expression. HFD feeding increased gene expression of inflammatory markers in the adipose tissue of WT and Adipoq-/- mice. While niacin tended to decrease the expression of inflammatory markers in WT mice, niacin increased their expression in HFD-fed Adipoq-/- mice. Therefore, our results indicate that the absence of adiponectin alters the effects of niacin on markers of adipose tissue inflammation in HFD-fed mice, suggesting that the effects of niacin on tissue cytokines may involve adiponectin.

Purpose/objectives The coronavirus disease 2019 (COVID-19) pandemic arguably represents the worst public health crisis of the 21st century. However, no empirical study currently exists in the literature that examines the impact of the COVID-19 pandemic on dental education. This study evaluated the impact of COVID-19 on dental education and dental students' experience. Methods An anonymous online survey was administrated to professional dental students that focused on their experiences related to COVID-19. The survey included questions about student demographics, protocols for school reopening and student perceptions of institutional responses, student concerns, and psychological impacts. Results Among the 145 respondents, 92.4% were pre-doctoral dental students and 7.6% were orthodontic residents; 48.2% were female and 12.6% students lived alone during the school closure due to the pandemic. Students' age ranged from 23 to 39 years. Younger students expressed more concerns about their emotional health (P = 0.01). In terms of the school's overall response to COVID-19, 73.1% students thought it was effective. The majority (83%) of students believed that social distancing in school can minimize the development of COVID-19. In general, students felt that clinical education suffered after transitioning to online but responded more positively about adjustments to other online curricular components. Conclusions The COVID-19 pandemic significantly impacted dental education. Our findings indicate that students are experiencing increased levels of stress and feel their clinical education has suffered. Most students appear comfortable with technology adaptations for didactic curriculum and favor masks, social distancing, and liberal use of sanitizers.

Background Obesity is a major public health concern that can result from diets high in fat and sugar, including sugar sweetened beverages. A proposed treatment for dietary-induced obesity is time-restricted feeding (TRF), which restricts consumption of food to specific times of the 24-hour cycle. Although TRF shows great promise to prevent obesity and the development of chronic disease, the effects of TRF to reverse metabolic changes and the development of NAFLD in animal models of a Western diet with sugary water consumption is not known. Objective The objective of the current study was to evaluate the role of TRF in the treatment of obesity and NAFLD through examination of changes in metabolic and histopathologic parameters. Methods To better understand the role of TRF in the treatment of obesity and NAFLD, we investigated the metabolic phenotype and NAFLD parameters in a mouse model of NAFLD in which obesity and liver steatosis are induced by a Western Diet (WD): a high-fat diet of lard, milkfat and Crisco with sugary drinking water. Mice were subjected to a short-term (4-weeks) and long-term (10-weeks) TRF in which food was restricted to 9 h at night. Results Prior to TRF treatment, the WD mice had increased body mass, and exhibited less activity, and higher average daytime energy expenditure (EE) than chow fed mice. Approximately 4- and 10-weeks following TFR treatment, WD-TRF had moderate but not statistically significant weight loss compared to WD-ad libitum (WD-AL) mice. There was a modest but significant reduction in the inguinal adipose tissue weight in both WD-TRF groups compared to the WD-AL groups; however, there was no difference in epididymal and retroperitoneal adipose tissue mass or adipocyte size distribution. In contrast, the diet-induced increase in normalized liver tissue weight, hepatic triglyceride, and NAFLD score was partially abrogated in the 4-week WD-TRF mice, while systemic insulin resistance was partially abrogated and glucose intolerance was completely abrogated in the 10-week WD-TRF mice. Importantly, WD-induced metabolic dysfunction (substrate utilization, energy expenditure, and activity) was partially abrogated by 4- and 10-week TRF. Conclusions Our results support the hypothesis that TRF aids in reducing the detrimental metabolic effects of consuming a WD with sugary drinking water but does not ameliorate obesity.

The shared social context created in a marriage may be important in motivating engagement in health behaviors, but spousal influence may not be uniformly applied. Our goal was to examine how spouses discuss health behaviors relevant for colorectal cancer (CRC) risk-reduction to better understand how spouses exert or fail to exert influence. In this pilot study, first degree relatives of CRC patients and their spouses completed demographic and self-reported health questionnaires. After a genetic counseling session regarding risk and risk reduction, couples engaged in a semi-structured discussion task to discuss lifestyle choices they currently undertake or could undertake to reduce risk. Demographic and health data was analyzed using descriptive statistics. Using a directed content analysis based on the transtheoretical model of behavior change, we coded discussion transcripts for depth and direction of talk for seven behavioral CRC risk factors. Spouses engaged in several strategies to reduce their risk for CRC, and problem-solved together to increase these preventative efforts. All couples mentioned diet and exercise as important factors in CRC risk; however, other risk factors received less attention. Despite evidence of support and encouragement, spouses ignored, minimized, or negated the importance of some health behaviors. Spousal influence could be an important tool to improve participation in health behaviors, but more guidance may be necessary to hold couples accountable to evidence-based guidelines to reduce risk. Health care providers should address couples as a unit to assess and address health behaviors.

Obesity is a major public health concern and overconsumption of unhealthy fats and sugary beverages are contributing factors. Time-restricted feeding can reduce obesity-associated pathophysiological parameters by limiting the time of food consumption; however, the effects of time-restricted sugary water consumption are unknown. To examine whether liquid calorie restriction impacts metabolic health, we measured metabolic parameters in mice provided liquid sugar at various intervals during the active phase. The control (Con) group received tap water, the adlibitum fructose-glucose (ALFG) group received ad libitumsugar water and the early fructose-glucose (EFG) and late fructose-glucose (LFG) groups received liquid sugar during the first and last six hours of the active period, respectively. Each group was given free access to chow. Zeitgeber time (ZT) notation was used to set all experimental time points to lights on as ZT 0. The ALFG group exhibited elevated body and adipose tissue weights compared to the other groups and increased hepatic steatosis compared to the Con group. The ALFG group consumed more calories than the other groups during ZT 6-11, indicating that this window may be critical in the promotion of weight gain from liquid sugar consumption. The EFG group exhibited higher levels of energy expenditure than the Con and LFG groups during the first half of the active period (ZT 12-17); however, there was no difference among the groups during the second half of the active period (ZT18-23). In contrast, the EFG group exhibited lower respiratory exchange ratio than other groups during the inactive period as well as the second half of the active period, indicating that the EFG group had greater metabolic flexibility and utilized lipids when carbohydrates from liquid sugar were not available. Additionally, the EFG group was more insulin tolerant than the ALFG and Con groups. Our results support the hypothesis that time-restricted liquid calorie restriction aids in reducing the detrimental metabolic effects of sugary drink consumption.

Objective Methionine restriction (MR) decreases inflammation and improves markers of metabolic disease in rodents. MR also increases hepatic and circulating concentrations of fibroblast growth factor 21 (FGF21). Emerging evidence has suggested that FGF21 exerts anti-inflammatory effects. The purpose of this study was to determine the role of FGF21 in mediating the MR-induced reduction in inflammation. Methods Wild-type and Fgf21-/- mice were fed a high-fat (HF) control or HF-MR diet for 8 weeks. In a separate experiment, mice were fed a HF diet (HFD) for 10 weeks. Vehicle or recombinant FGF21 (13.6 µg/d) was administered via osmotic minipump for an additional 2 weeks. Inflammation and metabolic parameters were measured. Results Fgf21-/- mice were more susceptible to HFD-induced inflammation, and MR reduced inflammation in white adipose tissue (WAT) and liver of Fgf21-/- mice. MR downregulated activity of signal transducer and activator of transcription 3 in WAT of both genotypes. FGF21 administration reduced hepatic lipids and blood glucose concentrations. However, there was little effect of FGF21 on inflammatory gene expression in liver or adipose tissue or circulating cytokines. Conclusions MR reduces inflammation independent of FGF21 action. Endogenous FGF21 is important to protect against the development of HFD-induced inflammation in liver and WAT, yet administration of low-dose FGF21 has little effect on markers of inflammation.

nonalcoholic fatty liver disease (NAFLD), an obesity and insulin resistance associated clinical condition - ranges from simple steatosis to nonalcoholic steatohepatitis. To model the human condition, a high-fat Western diet that includes liquid sugar consumption has been used in mice. Even though liver pathophysiology has been well characterized in the model, little is known about the metabolic phenotype (e.g., energy expenditure, activity, or food intake). Furthermore, whether the consumption of liquid sugar exacerbates the development of glucose intolerance, insulin resistance, and adipose tissue dysfunction in the model is currently in question. In our study, a high-fat Western diet (HFWD) with liquid sugar [fructose and sucrose (F/S)] induced acute hyperphagia above that observed in HFWD-fed mice, yet without changes in energy expenditure. Liquid sugar (F/S) exacerbated HFWD-induced glucose intolerance and insulin resistance and impaired the storage capacity of epididymal white adipose tissue (eWAT). Hepatic TG, plasma alanine aminotransferase, and normalized liver weight were significantly increased only in HFWD+F/S-fed mice. HFWD+F/S also resulted in increased hepatic fibrosis and elevated collagen 1a2, collagen 3a1, and TGFβ gene expression. Furthermore, HWFD+F/S-fed mice developed more profound eWAT inflammation characterized by adipocyte hypertrophy, macrophage infiltration, a dramatic increase in crown-like structures, and upregulated proinflammatory gene expression. An early hypoxia response in the eWAT led to reduced vascularization and increased fibrosis gene expression in the HFWD+F/S-fed mice. Our results demonstrate that sugary water consumption induces acute hyperphagia, limits adipose tissue expansion, and exacerbates glucose intolerance and insulin resistance, which are associated with NAFLD progression.

Nonalcoholic fatty liver disease (NAFLD) is a very common disorder affecting between 20 and 30% of adults in the United States. However, there is no effective pharmacotherapy for treating NAFLD. Niacin, a water-soluble vitamin (B3), at pharmacological doses, decreases hepatic triglyceride (TG) content in NAFLD through inhibition of diacylglycerol acyltransferase 2, a key enzyme that catalyzes the final step in TG synthesis. Alternatively, some studies indicate that niacin induces fatty liver in high-fat diet (HFD)-fed rats. Therefore, in this study we investigated whether niacin is beneficial in treating NAFLD in two strains of mice, C57BL/6J (B6) and B6129SF2/J (B6129) mice, with 20 weeks of HFD feeding. Niacin treatment was started from week 5 until the end of the study. Niacin treatment increased normalized liver weight, hepatic TG content and NAFLD score in HFD-fed B6129 mice but had no impact on B6 mice. Metabolomics analysis revealed that in B6129 mice, 4-hydroxyphenylpyruvic acid (4-HPP), which is associated with fatty acid oxidation, did not change with HFD feeding but significantly decreased with niacin treatment. Lipidomics analysis discovered that the abundance of phosphocholine (PC), which is critical for very low-density lipoprotein (VLDL)–TG production and secretion, was decreased in HFD-fed B6129 with niacin treatment. In conclusion, niacin had no impact on diet-induced NAFLD development in B6 mice but potentiated hepatic steatosis in HFD-fed B6129 mice due to impaired fatty acid oxidation and decreased VLDL-TG production and secretion.

Obesity is a major public health concern and overconsumption of unhealthy fats and sugary beverages are contributing factors. Time-restricted feeding can reduce obesity-associated pathophysiological parameters by limiting the time of food consumption; however, the effects of time-restricted sugary water consumption are unknown. To examine whether liquid calorie restriction impacts metabolic health, we measured metabolic parameters in mice provided liquid sugar at various intervals during the active phase. The control (Con) group received tap water, the adlibitum fructose-glucose (ALFG) group received ad libitumsugar water and the early fructose-glucose (EFG) and late fructose-glucose (LFG) groups received liquid sugar during the first and last six hours of the active period, respectively. Each group was given free access to chow. Zeitgeber time (ZT) notation was used to set all experimental time points to lights on as ZT 0. The ALFG group exhibited elevated body and adipose tissue weights compared to the other groups and increased hepatic steatosis compared to the Con group. The ALFG group consumed more calories than the other groups during ZT 6-11, indicating that this window may be critical in the promotion of weight gain from liquid sugar consumption. The EFG group exhibited higher levels of energy expenditure than the Con and LFG groups during the first half of the active period (ZT 12-17); however, there was no difference among the groups during the second half of the active period (ZT18-23). In contrast, the EFG group exhibited lower respiratory exchange ratio than other groups during the inactive period as well as the second half of the active period, indicating that the EFG group had greater metabolic flexibility and utilized lipids when carbohydrates from liquid sugar were not available. Additionally, the EFG group was more insulin tolerant than the ALFG and Con groups. Our results support the hypothesis that time-restricted liquid calorie restriction aids in reducing the detrimental metabolic effects of sugary drink consumption.

Objective Human papillomavirus (HPV) infects millions of men and women annually and is a substantial contributing factor in many cancers including oral, penile, anal, and cervical. Vaccination can reduce risk but adherence nationwide and, particularly in highly religious states, is suboptimal. Religious principles of abstinence before marriage and total fidelity following marriage may create a belief of protection through adherence to religious guidelines. However, while one partner may remain monogamous, one cannot be assured of their partner's behavior both before and after marriage. These misconceptions may create a barrier to religious youth's adherence to vaccine recommendations. Methods We sampled single young adults, age 18 to 25 years, from a Christian university classified as highly religious and a university not categorized as highly religious. Results Highly religious young adults demonstrated low knowledge of HPV and HPV vaccination. High religious beliefs were associated with lower HPV vaccination adherence. Conclusions Understanding the role religious beliefs have on vaccine adherence can help in the creation of campaigns that specifically address these issues. Campaigns to increase vaccination should address misconceptions of religious youth's feelings of imperviousness to sexually transmitted diseases.

Pharmacologically, FGF-21 reduces body weight, increases insulin sensitivity, and reduces hepatic lipids in rodents. Preclinical studies suggest that FGF-21 may exert anti-inflammatory effects. We aimed to determine 1) whether endogenous FGF-21 provides protective effects against high-fat diet (HFD)-induced inflammation, and 2) whether low-dose administration of FGF-21 reverses HFD-induced inflammation and hepatic steatosis. In experiment #1, wild type (WT) and FGF-21-/- mice (n=8/group) were fed a HFD for 15 weeks. RT-PCR analysis showed that despite weighing slightly less than the WT mice, the FFG-21-/- mice were more susceptible to HFD-induced inflammation of the liver and white adipose tissue (WAT). To test whether administration of FGF-21 provides protection from HFD-induced inflammation, in Experiment #2, 20 male C57BL/6J mice were fed a HFD for 10 weeks. After 10 weeks of HFD feeding, mice were administered vehicle (saline + 0.1% BSA; n=10) or recombinant human FGF-21 (R and D Systems; n=10; 0.3 mg/kg/day) for 14 days via subcutaneous osmotic minipumps. There was no effect of FGF-21 administration on body weight. Histological analysis of WAT showed no effect of FGF-21 on adipocyte size, and no effect on crown-like structure number. Confirming this lack of effect of FGF-21 on inflammation, RT-PCR analyses of liver and WAT showed comparable mRNA expression of inflammatory markers, including Adgre1, Itgam, Itgax, Ccl2, Il1b, and Tnf in the vehicle- and FGF-21 treated groups. Despite having no effect on inflammation, FGF-21 significantly reduced fasting blood glucose levels. Histological evaluation of liver showed that low-dose FGF-21 administration improved nonalcoholic steatohepatitis score, attributed to decreased microvesicular steatosis. In conclusion, endogenous FGF-21 confers some protection against obesity-induced inflammation, and low-dose FGF-21 administration decreases hepatic steatosis independent of changes in body weight. Disclosure S. Sharma: None. S. Jung: None. E. Graff: None. T.W. Gettys: None. D. Wanders: None.

Pharmacological doses of niacin improve adipose tissue (AT) inflammation and nonalcoholic fatty liver disease (NAFLD) in rodents chronically fed a high-fat diet (HFD). However, recent mouse studies have demonstrated significant metabolic changes in different strains of mice fed a HFD. Therefore, the aim of this study was to assess the effect of niacin on both AT inflammation and liver steatosis in two mouse strains, C57BL6/J (B6) and B6129SF2/J (B6129), under HFD feeding. Thirty-two male B6 and 32 male B6129 mice were randomized into four groups: Chow/Vehicle (CV), Chow/Niacin (CN), HFD/Vehicle (HV), and HFD/Niacin (HN). They were fed either a chow (10% fat) or HFD (60% fat) for 20 weeks. Niacin (360 mg/kg/day) or vehicle was added to the drinking water from week 5 until the end of the study. As expected, HFD-fed mice gained more weight than chow-fed mice in both strains, with no difference in weight gain between strains. Crown-like structure (CLS) number, a hallmark of AT inflammation, was increased in HV mice of both strains compared to CV mice. In addition, HV B6 mice had higher CLS number than HV B6129 mice. In B6129 mice, niacin decreased CLS number in HN compared to HV mice, while this decrease was not observed in B6 mice. Liver weight to body weight (L/B) ratio, liver triglyceride (TG) content and NASH score was increased in HV compared to CV B6 mice. In contrast, in B6129 mice, only NASH score was increased in HV compared to CV controls. Niacin had no impact on L/B ratio, TG content, or NASH score in B6 mice. However, in B6129 mice, niacin increased all three parameters in HN compared to HV mice. In conclusion, there are strain differential effects on AT inflammation and NAFLD induced by HFD feeding. Interestingly, liver steatosis is significantly increased in HFD-fed B6129 mice treated with niacin. This increase is potentially due to methyl deficiency, as niacin is a potent hepatic methyl consumer and 129 mice are more sensitive to methyl deficiency. Disclosure H. Fang: None. E. Graff: None. Z. Li: None. R.L. Judd: None.

A 7-year-old castrated male Pomeranian was evaluated on emergency for diagnostic work-up and treatment for acute nonpainful paraparesis. The neurologic examination suggested a L4-S3 myelopathy, but physical examination revealed lack of femoral pulses and rectal hypothermia, as well as a grade II/VI systolic heart murmur, so ischemic neuromyopathy was suspected. Clinicopathologic analysis revealed increased muscle enzymes and proteinuria. Abdominal ultrasonography confirmed aortic thromboembolism (ATE), and surgical histopathology diagnosed necrotizing pancreatitis. Surgical aortic thrombectomy was performed, and antithrombotic therapy was instituted. Pancreatitis was treated supportively. The dog was discharged to the owners after 10 days of hospitalization. Recheck examination 6 weeks after initial presentation revealed a normal neurologic examination and normal femoral pulses. The patient has had no further bouts of pancreatitis and remains neurologically normal 5 years after initial presentation. Canine ATE is relatively rare compared to the feline counterpart. Directed therapy for feline ATE is often not recommended, as underlying conditions are oftentimes ultimately fatal. Underlying etiologies for canine ATE include cardiovascular disease and endocrinopathies, but canine ATE secondary to pancreatitis has not yet been reported. Surgical removal of aortic thromboembolus should be considered as curative for pelvic limb dysfunction in the canine patient without a terminal underlying disease.

Evaluation of the bone marrow is needed for complete staging in dogs with multicentric large-cell lymphoma, but is often omitted in clinical practice.The objective was to determine if routine peripheral blood findings, including microscopic evaluation of blood smears, can predict the presence of bone marrow involvement in dogs with lymphoma.Hematologic data including evaluation of blood smears and bone marrow aspirates from 107 dogs newly diagnosed with large-cell lymphoma were retrospectively evaluated. Neoplastic lymphocytes were identified based on cell size, nuclear size, chromatin pattern, and the presence of nucleoli. Positive specimens were defined as having ≥ 10% neoplastic lymphocytes. Two groups were established based on the presence or absence of lymphoma in the bone marrow. Variables (positive blood smear, HCT, platelet count, and total and differential WBC counts) were evaluated to determine if they were predictive of bone marrow involvement using univariate and multivariate logistic models.Thrombocytopenia and the presence of 10% neoplastic lymphocytes on blood smears were identified as significant variables for predicting the presence of bone marrow involvement. When considered independently, either a positive blood smear or thrombocytopenia had low sensitivity (60%) and moderate specificity (89% and 87%, respectively). Sensitivity increased when these variables were evaluated together (80%).In dogs with multicentric large-cell lymphoma, thrombocytopenia or the presence of neoplastic lymphocytes in circulation is suggestive of bone marrow involvement, but not definitive. Normal peripheral blood findings do not exclude the possibility of lymphoma in the bone marrow.

To guide users who attempt to deploy wireless networks in military applications, there is an evolving need for developing systematic methodologies to analyze/predict the performance of mobile ad hoc networks (MANETs). In addition, the advance in cognitive networking research provides opportunities for exploiting unused spectrum to optimize throughput of MANETs. However, with the increasing number of parameters/constraints, there is even a more demanding need to develop automated methodologies to design/tune such networks. In this work, we study the concepts and challenges for automatic design/re-configuration of cognitive MANETs, in addition to proposing design automation algorithms. The paper is divided into two parts. In the first part, we describe the design objectives, imposed constraints, and involved parameters in MANET design. We discuss how cognitive techniques can be employed to exploit the unused spectrum in military architectures. We then discuss the challenges that face the design/re-configuration of a cognitive network and their implications at different network layers. We also describe possible implementation options for designing MANETs that employ cognitive features at all layers. In the second part of this work, we propose design automation algorithms for optimally setting parameters to achieve a desired objective and satisfy certain constraints. Despite providing the optimal configuration, the simple approach of testing all possible combinations of parameter settings has significant time complexity (the COMB approach). Thus, we propose a novel heuristic (Sequential Parameter Optimization or SEPO) for searching through the possible parameter settings and selecting the best design options. SEPO is efficient in terms of both convergence speed and parameter tuning. We also discuss the foundation for using supervised learning to speed up the design (search) process. By evaluating realistic design of military-like scenarios that require optimizing a diverse set of metrics, we show that SEPO generates comparable results to the optimal, straightforward (slow-converging) COMB approach that is based on exhaustive search.

Spatial/temporal controls of development are regulated by the homeotic (HOX) gene complex and require integration with oncogenes and tumour suppressors regulating cell cycle exit. Spontaneously derived neoplastic canine mammary carcinoma cell models were investigated to determine if HOX expression profiles were associated with neoplasia as HOX genes promote neoplastic potential in human cancers. Comparative assessment of human and canine breast cancer expression profiles revealed remarkable similarity for all four paralogous HOX gene clusters and several unlinked HOX genes. Five canine HOX genes were overexpressed with expression profiles consistent with oncogene-like character (HOXA1, HOXA13, HOXD4, HOXD9 and SIX1) and three HOX genes with underexpressed profiles (HOXA11, HOXC8 and HOXC9) were also identified as was an apparent nonsense mutation in HOXC6. This data, as well as a comparative analysis of similar data from human breast cancers suggested expression of selected HOX genes in canine mammary carcinoma could be contributing to the neoplastic phenotype.

We present a software library that aids in the design of mobile ad hoc networks (MANET). The OMAN design engine works by taking a specification of network requirements and objectives, and allocates resources which satisfy the input constraints and maximize the communication performance objective. The tool is used to explore networking design options and challenges, including: power control, adaptive modulation, flow control, scheduling, mobility, uncertainty in channel models, and cross-layer design. The unaddressed niche which OMAN seeks to fill is the general framework for optimization of any network resource, under arbitrary constraints, and with any selection of multiple objectives. While simulation is an important part of measuring the effectiveness of implemented optimization techniques, the novelty and focus of OMAN is on proposing novel network design algorithms, aggregating existing approaches, and providing a general framework for a network designer to test out new proposed resource allocation methods. In this paper, we present a high-level view of the OMAN architecture, review specific mathematical models used in the network representation, and show how OMAN is used to evaluate tradeoffs in MANET design. Specifically, we cover three case studies of optimization. The first case is robust power control under uncertain channel information for a single physical layer snapshot. The second case is scheduling with the availability of directional radiation patterns. The third case is optimizing topology through movement planning of relay nodes.

The d-mannonate dehydratase (ManD) subgroup of the enolase superfamily contains members with varying catalytic activities (high-efficiency, low-efficiency, or no activity) that dehydrate d-mannonate and/or d-gluconate to 2-keto-3-deoxy-d-gluconate [Wichelecki, D. J., et al. (2014) Biochemistry 53, 2722-2731]. Despite extensive in vitro characterization, the in vivo physiological role of a ManD has yet to be established. In this study, we report the in vivo functional characterization of a high-efficiency ManD from Caulobacter crescentus NA1000 (UniProt entry B8GZZ7) by in vivo discovery of its essential role in d-glucuronate metabolism. This in vivo functional annotation may be extended to ~50 additional proteins.

Unlike commercial MANET applications, tactical networks are typically hierarchical and involve heterogeneous types of radio communications. Future tactical networks also require cognitive functions across the protocol stack to exploit scarce spectrum and dynamically adapt functions and configuration settings. In this work we highlight the need for novel design tools for cognitive tactical networks. We define a system design model that will provide the foundation for generic network design problem formulations via the use of cognitive techniques covering both dynamic frequency adaptations and machinelearning- related aspects of cognition. We use the system model to identify several potential cognitive design knobs and describe how the different design knobs can potentially be adjusted at different timescales of operation. These knobs are used in formulating a cognitive network design problem. Finally, we discuss how a network designer can potentially benefit from the proposed model result, a cognitive network design toolset we have recently developed.