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26.  Prevalence and diversity of H9N2 avian influenza in chickens of Northern Vietnam, 2014 
Despite their classification as low pathogenicity avian influenza viruses (LPAIV), A/H9N2 viruses cause significant losses in poultry in many countries throughout Asia, the Middle East and North Africa. To date, poultry surveillance in Vietnam has focused on detection of influenza H5 viruses, and there is limited understanding of influenza H9 epidemiology and transmission dynamics. We determined prevalence and diversity of influenza A viruses in chickens from live bird markets (LBM) of 7 northern Vietnamese provinces, using pooled oropharyngeal swabs collected from October to December 2014. Screening by real time RT-PCR revealed 1207/4900 (24.6%) of pooled swabs to be influenza A virus positive; overall prevalence estimates after accounting for pooling (5 swabs/pools) were 5.8% (CI 5.4–6.0). Subtyping was performed on 468 pooled swabs with M gene Ct < 26. No influenza H7 was detected; 422 (90.1%) were H9 positive; and 22 (4.7%) were H5 positive. There was no evidence was of interaction between H9 and H5 virus detection rates. We sequenced 17 whole genomes of A/H9N2, 2 of A/H5N6, and 11 partial genomes. All H9N2 viruses had internal genes that clustered with genotype 57 and were closely related to Chinese human isolates of A/H7N9 and A/H10N8. Using a nucleotide divergence cutoff of 98%, we identified 9 distinct H9 genotypes. Phylogenetic analysis suggested multiple introductions of H9 viruses to northern Vietnam rather than in-situ transmission. Further investigations of H9 prevalence and diversity in other regions of Vietnam are warranted to assess H9 endemicity elsewhere in the country.
Highlights
•We report detection of highly pathogenic avian influenza (HPAI) from healthy chickens in Live Bird Markets of Vietnam. Because all breeds of domestic chickens are extremely susceptible to HPAI, we speculate that HPAI detections from market chickens may reflect infections that occur after arrival in the market. Alternatively, shedding of HPAI from healthy birds may reflect vaccine-induced protective immunity that mitigates disease but does not block viral infection.•As many as 49% of all pooled surveillance swabs were positive for influenza A virus, corresponding to an overall Influenza A prevalence of 5.45% (95% Confidence Interval 5.4-6.0%).•Low pathogenicity avian influenza (LPAI) H9N2 accounted for the vast majority of all influenza A detections in market chickens sampled from 9 northern provinces.•To date there is no evidence to suggest an interaction effect between circulation of H5 and H9 viruses; however sampling strategies that involve pooling of surveillance swabs from multiple birds greatly complicates the assessment of co-infection rates or evaluation of epidemiological associations.
doi:10.1016/j.meegid.2016.06.038
PMCID: PMC5036934  PMID: 27340015
LPAI, low pathogenicity avian influenza; HPAI, highly pathogenic avian influenza; FAO, Food and Agriculture Organization of the United Nations; LBM, live bird market; Avian influenza; Vietnam; H9N2; Poultry; Chicken; H5; Zoonotic
28.  Muscarinic type 3 receptor autoantibodies are associated with anti-SSA/Ro autoantibodies in Sjögren’s syndrome 
Anti-muscarinic type 3 receptor autoantibodies (anti-M3R) are reported as potential inhibitors of saliva secretion in Sjögren’s syndrome (SjS). However, despite extensive efforts to establish an anti-M3R detection method, there is no clinical test available for these autoantibodies. The purpose of this study was to propose inclusion of anti-M3R testing for SjS diagnosis through investigation of their prevalence using a modified In-Cell Western (ICW) assay. A stable cell line expressing human M3R tagged with GFP (M3R-GFP) was established to screen unadsorbed and adsorbed plasma from primary SjS (n = 24), rheumatoid arthritis (RA, n = 18), systemic lupus erythematosus (SLE, n = 18), and healthy controls (HC, n = 23). Anti-M3R abundance was determined by screening for the intensity of human IgG interacting with M3R-GFP cells by ICW assay, as detected by an anti-human IgG IRDye800-conjugated secondary antibody and normalized to GFP. Method comparisons and receiver-operating-characteristic (ROC)-curve analyses were performed to evaluate the diagnostic value of our current approaches. Furthermore, clinical parameters of SjS were also analyzed in association with anti-M3R. Anti-M3R was significantly elevated in SjS plasma in comparison with HC, SLE, or RA (P < 0.01). SjS anti-M3R intensities were greater than two-standard deviations above the HC mean for both unadsorbed (16/24, 66.67%) and adsorbed (18/24, 75%) plasma samples. Furthermore, anti-M3R was associated with anti-SjS-related-antigen A/Ro positivity (P = 0.0353). Linear associations for anti-M3R intensity indicated positive associations with focus score (R2 = 0.7186, P < 0.01) and negative associations with saliva flow rate (R2 = 0.3052, P < 0.05). Our study strongly supports our rationale to propose inclusion of anti-M3R for further testing as a non-invasive serological marker for SjS diagnosis.
doi:10.1016/j.jim.2016.07.003
PMCID: PMC5036946  PMID: 27460476
Sjögren’s syndrome; Autoantibodies; Muscarinic type 3 receptor; Sjögren’s syndrome antigen A
29.  Mapping paddy rice planting area in cold temperate climate region through analysis of time series Landsat 8 (OLI), Landsat 7 (ETM+) and MODIS imagery 
Accurate and timely rice paddy field maps with a fine spatial resolution would greatly improve our understanding of the effects of paddy rice agriculture on greenhouse gases emissions, food and water security, and human health. Rice paddy field maps were developed using optical images with high temporal resolution and coarse spatial resolution (e.g., Moderate Resolution Imaging Spectroradiometer (MODIS)) or low temporal resolution and high spatial resolution (e.g., Landsat TM/ETM+). In the past, the accuracy and efficiency for rice paddy field mapping at fine spatial resolutions were limited by the poor data availability and image-based algorithms. In this paper, time series MODIS and Landsat ETM+/OLI images, and the pixel- and phenology-based algorithm are used to map paddy rice planting area. The unique physical features of rice paddy fields during the flooding/open-canopy period are captured with the dynamics of vegetation indices, which are then used to identify rice paddy fields. The algorithm is tested in the Sanjiang Plain (path/row 114/27) in China in 2013. The overall accuracy of the resulted map of paddy rice planting area generated by both Landsat ETM+ and OLI is 97.3%, when evaluated with areas of interest (AOIs) derived from geo-referenced field photos. The paddy rice planting area map also agrees reasonably well with the official statistics at the level of state farms (R2 = 0.94). These results demonstrate that the combination of fine spatial resolution images and the phenology-based algorithm can provide a simple, robust, and automated approach to map the distribution of paddy rice agriculture in a year.
doi:10.1016/j.isprsjprs.2015.04.008
PMCID: PMC5042353  PMID: 27695195
Rice paddy; Cropland; Observation frequency; Data availability; Vegetation indices; Sanjiang Plain
30.  Infant, Control Thyself: Infants’ Integration of Multiple Social Cues to Regulate Their Imitative Behavior 
Cognitive development  2014;32:46-57.
This study investigated 15-month-old infants’ (N = 150) ability to self-regulate based on observing a social interaction between two adults. Infants were bystanders to a social exchange in which an Experimenter performed actions on objects and an Emoter expressed anger, as if they were forbidden acts. Next, the Emoter became neutral and her visual access to the infant was experimentally manipulated. The Emoter either: (a) left the room, (b) turned her back, (c) faced the infant but looked down at a magazine, or (d) faced and looked toward the infant. Infants were then presented with the test objects. When the previously angry Emoter was facing them, infants were hesitant to imitate the demonstrated acts in comparison to the other conditions. We hypothesize that infants integrated the emotional and visual-perceptual cues to determine whether the Emoter would get angry at them, and then regulated their behavior accordingly. Temperament was related to infants’ self-regulation –infants with higher impulsivity scores were more likely to perform the forbidden acts. Taken together, these findings provide insight into the roots of executive functions in late infancy.
doi:10.1016/j.cogdev.2014.04.004
PMCID: PMC5036936  PMID: 27682643
Emotion; imitation; executive function; gaze following; social referencing
31.  BSN723T Prevents Atherosclerosis and Weight Gain in ApoE Knockout Mice Fed a Western Diet 
WebmedCentral  2015;6(12):WMC005034.
Objective
This study tests the hypothesis that BSN723T can prevent the development of hyperlipidemia and atherosclerosis in ApoE-/- knockout mice fed a Western (high fat, high cholesterol, and high sucrose) diet. BSN723T is a combination drug therapy consisting of D-tagatose and dihydromyricetin (BSN723).
Background
D-tagatose has an antihyperglycemic effect in animal and human studies and shows promise as a treatment for type 2 diabetes and obesity. Many claims regarding BSN723's pharmacological activities have been made including anti-cancer, anti-diabetic, anti-hypertensive, anti-inflammatory, and anti-atherosclerotic effects. To our knowledge this is the first study that combines D-tagatose and BSN723 for the treatment of hyperlipidemia and the prevention of atherosclerosis.
Methods
ApoE-deficient mice were randomized into five groups with equivalent mean body weights. The mice were given the following diets for 8 weeks: Group 1 - Standard diet; Group 2 - Western diet; Group 3 - Western diet formulated with D-tagatose; Group 4 - Western diet formulated with BSN723; Group 5 - Western diet formulated with BSN723T. Mice were measured for weight gain, tissue and organ weights, total serum cholesterol and triglycerides and formation of atherosclerosis.
Results
The addition of D-tagatose, either alone or in combination with BSN723, prevented the increase in adipose tissue and weight gain brought on by the Western diet. Both D-tagatose and BSN723 alone reduced total cholesterol and the formation of atherosclerosis in the aorta compared to mice on the Western diet. Addition of BSN723 to D-tagatose (BSN723T) did not increase efficacy in prevention of increases in cholesterol or atherosclerosis compared to D-tagatose alone.
Conclusion
Addition of either D-tagatose or BSN723 alone to a Western diet prevented weight gain, increases in total serum cholesterol and triglycerides, and the formation of atherosclerosis. However, there was no additive or synergistic effect on the measured parameters with the combination BSN723T treatment.
PMCID: PMC5036941  PMID: 27683620
D-tagatose; D-lyxohexulose; dihydromyricetin; DLH; atheroma; sucrose; fat; ApoE-/-
32.  Sleep to forget: interference of fear memories during sleep 
Molecular psychiatry  2013;18(11):1166-1170.
Memories are consolidated and strengthened during sleep. Here we show that memories can also be weakened during sleep. We used a fear-conditioning paradigm in mice to condition footshock to an odor (conditioned stimulus (CS)). Twenty-four hours later, presentation of the CS odor during sleep resulted in an enhanced fear response when tested during subsequent wake. However, if the re-exposure of the CS odor during sleep was preceded by bilateral microinjections of a protein synthesis inhibitor into the basolateral amygdala, the subsequent fear response was attenuated. These findings demonstrate that specific fear memories can be selectively reactivated and either strengthened or attenuated during sleep, suggesting the potential for developing sleep therapies for emotional disorders.
doi:10.1038/mp.2013.121
PMCID: PMC5036945  PMID: 24081009
amygdala; anisomycin; behavioral freezing; extinction therapy; PTSD
33.  RENEW—a renal redesign project in predialysis patient care 
Clinical Kidney Journal  2016;9(5):748-754.
Background
An ageing population and geographical growth, along with an increase in the number of people that reside in specific location, are increasing the demand for renal replacement therapies. Hospital-based haemodialysis units are struggling to cope with the associated physical, staffing and cost demands. Home-based dialysis therapies are known to be more cost effective with superior social, physical health and survival outcomes.
Methods
‘RENEW, a renal redesign project, examined the pre-dialysis health care experience of renal patients to find opportunities to improve patient care outcomes and increase the uptake of home-based dialysis therapies. This article details two crucial parts of the approach to change management: (i) diagnostics—an inclusive, client focused, multidisciplinary approach to identify issues relating to the pre-dialysis journey—and (ii) solution design—an inclusive problem-solving approach to identify and marry solutions to the issues identified during diagnostics.
Results
Based on feedback from patients/caregivers and staff interviews, utilizing a clinical redesign methodology, a new model of care was developed, implemented and subsequently embedded into clinical practice. The results have been evident via improved care coordination, enhanced patient preparation for dialysis, improved patient psychosocial welfare and, importantly, an increased number of patients planned for and commencing home dialysis. This has empowered patients by giving them the confidence, knowledge and skills to be actively engaged in their own care. The project resulted in significant expenditure avoidance.
Conclusion
Change management strategies with successful implementation are vital components of evolving clinical practice to achieve both clinical and organizational goals.
doi:10.1093/ckj/sfw081
PMCID: PMC5036908  PMID: 27679723
change management; clinical redesign; dialysis; home dialysis
34.  Approach to atherosclerotic renovascular disease: 2016 
Clinical Kidney Journal  2016;9(5):713-721.
The management of atherosclerotic renal artery stenosis in patients with hypertension or impaired renal function remains a clinical dilemma. The current general consensus, supported by the results of the Angioplasty and Stenting for Renal Atherosclerotic Lesions and Cardiovascular Outcomes for Renal Artery Lesions trials, argues strongly against endovascular intervention in favor of optimal medical management. We discuss the limitations and implications of the contemporary clinical trials and present our approach and formulate clear recommendations to help with the management of patients with atherosclerotic narrowing of the renal artery.
doi:10.1093/ckj/sfw079
PMCID: PMC5036906  PMID: 27679718
atherosclerosis; chronic renal insufficiency; CKD; hypertension; renal artery stenosis
35.  Serum FGF23 levels may not be associated with serum phosphate and 1,25-dihydroxyvitamin D levels in patients with Fanconi syndrome–induced hypophosphatemia 
Clinical Kidney Journal  2016;9(5):677-681.
Fibroblast growth factor 23 (FGF23) is regulated by sustained phosphate supplementation and restriction. However, few studies have investigated FGF23 levels in patients with Fanconi syndrome. Therefore, we evaluated intact and C-terminal FGF23 and FGF23-associated parameters in four patients with Fanconi syndrome. Serum intact and C-terminal FGF23 levels were extremely low. Although serum phosphate and 1,25-dihydroxyvitamin D levels improved to or above the normal range within 1 year of treatment with oral phosphate and calcitriol, serum FGF23 levels remained low. Serum FGF23 levels in patients with Fanconi syndrome might be regulated by novel factors other than serum phosphate and 1,25-dihydroxyvitamin D levels.
doi:10.1093/ckj/sfw086
PMCID: PMC5036911  PMID: 27679714
CKD; FGF-23; vitamin D
36.  FGF23 in kidney transplant: the strange case of Doctor Jekyll and Mister Hyde 
Clinical Kidney Journal  2016;9(5):665-668.
During the last decade, a new view into the molecular mechanisms of chronic kidney disease-mineral bone disorder (CKD-MBD) has been proposed, with fibroblast growth factor 23 (FGF23) as a novel player in the field. Enhanced serum FGF23 levels cause a reduction in serum phosphate, together with calcitriol suppression and consequent hyperparathyroidism (HPT). In contrast, reduced serum FGF23 levels are associated with hyperphosphatemia, higher calcitriol levels and parathyroid hormone (PTH) suppression. In addition, serum FGF23 levels are greatly increased and positively correlated with serum phosphate levels in CKD patients. In this population, high serum FGF23 concentration seems to predict the occurrence of refractory secondary HPT and to be associated with higher mortality risk in incident haemodialysis patients. In living-donor kidney transplant recipients, a faster normalization of FGF23 and phosphate levels with a lower prevalence of HPT, may be considered a major pathway to investigate.
doi:10.1093/ckj/sfw072
PMCID: PMC5036904  PMID: 27679712
CKD-MBD; FGF23; PTH; secondary hyperparathyroidism
37.  Spatial and Temporal Variations of PM2.5 and Its Relation to Meteorological Factors in the Urban Area of Nanjing, China 
The serious air pollution problem has aroused widespread public concerns in China. Nanjing city, as one of the famous cities of China, is faced with the same situation. This research aims to investigate spatial and temporal distribution characteristics of fine particulate matter (PM2.5) and the influence of weather factors on PM2.5 in Nanjing using Spearman-Rank analysis and the Complete Ensemble Empirical Mode Decomposition with Adaptive Noise (CEEMDAN) method. Hourly PM2.5 observation data and daily meteorological data were collected from 1 April 2013 to 31 December 2015. The spatial distribution result shows that the Maigaoqiao site suffered the most serious pollution. Daily PM2.5 concentrations in Nanjing varied from 7.3 μg/m3 to 336.4 μg/m3. The highest concentration was found in winter and the lowest in summer. The diurnal variation of PM2.5 increased greatly from 6 to 10 a.m. and after 6 p.m., while the concentration exhibited few variations in summer. In addition, the concentration was slightly higher on weekends compared to weekdays. PM2.5 was found to exhibit a reversed relation with wind speed, relative humidity, and precipitation. Although temperature had a positive association with PM2.5 in most months, a negative correlation was observed during the whole period. Additionally, a high concentration was mainly brought with the wind with a southwest direction and several relevant factors are discussed to explain the difference of the impacts of diverse wind directions.
doi:10.3390/ijerph13090921
PMCID: PMC5036754  PMID: 27649227
PM2.5; spatial and temporal variations; meteorological factors; CEEMDAN; Nanjing
38.  Cutaneous Mycobacterium chelonae infection distal to the arteriovenous fistula 
Clinical Kidney Journal  2016;9(5):735-738.
A few single cases of Mycobacterium chelonae skin infection have been reported in haemodialysis patients. We report three additional cases that share peculiar clinical characteristics, pointing to diagnostic clues. All three cases presented as erythematous nodules developing distally to a proximal arteriovenous fistula (AVF). This presentation was identical to that of two published cases. A survey of all Belgian haemodialysis units during the period 2007–11 yields an estimated incidence of ∼0.9/10 000 patient-years. Although the source of M. chelonae remains unclear, this specific clinical presentation should be added to the listing of potential complications of an AVF and should be recognized, as it is fully treatable if diagnosed by culture and tissue biopsy.
doi:10.1093/ckj/sfw073
PMCID: PMC5036905  PMID: 27679721
arteriovenous fistula; haemodialysis; Mycobacterium chelonae
39.  Applying effective teaching and learning techniques to nephrology education 
Clinical Kidney Journal  2016;9(5):755-762.
The interest in nephrology as a career has declined over the last several years. Some of the reasons cited for this decline include the complexity of the specialty, poor mentoring and inadequate teaching of nephrology from medical school through residency. The purpose of this article is to introduce the reader to advances in the science of adult learning, illustrate best teaching practices in medical education that can be extrapolated to nephrology and introduce the basic teaching methods that can be used on the wards, in clinics and in the classroom.
doi:10.1093/ckj/sfw083
PMCID: PMC5036910  PMID: 27679724
learning; medical education; nephrology; teaching
40.  Iohexol plasma clearance for measuring glomerular filtration rate in clinical practice and research: a review. Part 1: How to measure glomerular filtration rate with iohexol? 
Clinical Kidney Journal  2016;9(5):682-699.
While there is general agreement on the necessity to measure glomerular filtration rate (GFR) in many clinical situations, there is less agreement on the best method to achieve this purpose. As the gold standard method for GFR determination, urinary (or renal) clearance of inulin, fades into the background due to inconvenience and high cost, a diversity of filtration markers and protocols compete to replace it. In this review, we suggest that iohexol, a non-ionic contrast agent, is most suited to replace inulin as the marker of choice for GFR determination. Iohexol comes very close to fulfilling all requirements for an ideal GFR marker in terms of low extra-renal excretion, low protein binding and in being neither secreted nor reabsorbed by the kidney. In addition, iohexol is virtually non-toxic and carries a low cost. As iohexol is stable in plasma, administration and sample analysis can be separated in both space and time, allowing access to GFR determination across different settings. An external proficiency programme operated by Equalis AB, Sweden, exists for iohexol, facilitating interlaboratory comparison of results. Plasma clearance measurement is the protocol of choice as it combines a reliable GFR determination with convenience for the patient. Single-sample protocols dominate, but multiple-sample protocols may be more accurate in specific situations. In low GFRs one or more late samples should be included to improve accuracy. In patients with large oedema or ascites, urinary clearance protocols should be employed. In conclusion, plasma clearance of iohexol may well be the best candidate for a common GFR determination method.
doi:10.1093/ckj/sfw070
PMCID: PMC5036902  PMID: 27679715
glomerular filtration rate; iohexol
41.  Favorable lifestyle before diagnosis associated with lower risk of screen-detected advanced colorectal neoplasia 
World Journal of Gastroenterology  2016;22(27):6276-6286.
AIM: To investigate the association between adherence to health recommendations and detection of advanced colorectal neoplasia (ACN) in colorectal cancer (CRC) screening.
METHODS: A total of 14832 women and men were invited to CRC screening, 6959 in the fecal immunochemical test arm and 7873 in the flexible sigmoidoscopy arm. These were also sent a self-reported lifestyle questionnaire to be completed prior to their first CRC screening. A lifestyle score was created to reflect current adherence to healthy behaviors in regard to smoking, body mass index, physical activity, alcohol consumption and food consumption, and ranged from zero (poorest) to six (best). Odds ratios (ORs) and 95%CIs were calculated using multivariable logistic regression to evaluate the association between the single lifestyle variables and the lifestyle score and the probability of detecting ACN.
RESULTS: In all 6315 women and men completed the lifestyle questionnaire, 3323 (53%) in the FIT arm and 2992 (47%) in the FS arm. This was 89% of those who participated in screening. ACN was diagnosed in 311 (5%) participants of which 25 (8%) were diagnosed with CRC. For individuals with a lifestyle score of two, three, four, and five-six, the ORs (95%CI) for the probability of ACN detection were 0.82 (0.45-1.16), 0.43 (0.28-0.73), 0.41 (0.23-0.64), and 0.41 (0.22-0.73), respectively compared to individuals with a lifestyle score of zero-one. Of the single lifestyle factors, adherence to non-smoking and moderate alcohol intake were associated with a decreased probability of ACN detection compared to being a smoker or having a high alcohol intake 0.53 (0.42-0.68) and 0.63 (0.43-0.93) respectively.
CONCLUSION: Adopted healthy behaviors were inversely associated with the probability of ACN detection. Lifestyle assessment might be useful for risk stratification in CRC screening.
doi:10.3748/wjg.v22.i27.6276
PMCID: PMC4945986  PMID: 27468217
Screening; Colorectal neoplasia; Lifestyle; Prevention; Health recommendations
42.  Editorial: Mathematical and Statistics Anxiety: Educational, Social, Developmental and Cognitive Perspectives 
Frontiers in Psychology  2016;7:1083.
doi:10.3389/fpsyg.2016.01083
PMCID: PMC4954845  PMID: 27493636
anxiety specificity; developmental change; emotional factors; gender differences; mathematical anxiety; mathematics performance; measurement
43.  Rationale and Design of a Patient-Centered Medical Home Intervention for Patients with End-stage Renal Disease on Hemodialysis 
In the U.S., more than 400,000 individuals with end-stage renal disease (ESRD) require hemodialysis (HD) for renal replacement therapy. ESRD patients experience a high burden of morbidity, mortality, resource utilization, and poor quality of life (QOL). Under current care models ESRD patients receive fragmented care from multiple providers at multiple locations. The Patient-Centered Medical Home (PCMH) is a team approach, providing coordinated care across the healthcare continuum. While this model has shown some early benefits for complex chronic diseases such as diabetes, it has not been applied to HD patients. This study is a non-randomized quasi-experimental intervention trial implementing a Patient-Centered Medical Home for Kidney Disease (PCMH-KD). The PCMH-KD extends the existing dialysis care team (comprised of a nephrologist, dialysis nurse, dialysis technician, social worker, and dietitian) by adding a general internist, pharmacist, nurse coordinator, and a community health worker, all of whom will see the patients together, and separately, as needed. The primary goal is to implement a comprehensive, multidisciplinary care team to improve care coordination, quality of life, and healthcare use for HD patients. Approximately 240 patients will be recruited from two sites; a non-profit university-affiliated dialysis center and an independent for-profit dialysis center. Outcomes include: i) patient-reported outcomes, including QOL and satisfaction; ii) clinical outcomes, including blood pressure and diet; iii) healthcare use, including emergency room visits and hospitalizations; and iv) staff perceptions. Given the significant burden that patients with ESRD on HD experience, enhanced care coordination provides an opportunity to reduce this burden and improve QOL.
doi:10.1016/j.cct.2015.02.006
PMCID: PMC4947379  PMID: 25735489
clinical trial; medical home; quality of life
44.  PF-05231023, a long-acting FGF21 analogue, decreases body weight by reduction of food intake in non-human primates 
PF-05231023, a long-acting FGF21 analogue, is a promising potential pharmacotherapy for the treatment of obesity and associated comorbidities. Previous studies have shown the potential of FGF21 and FGF21-like compounds to decrease body weight in mice, non-human primates, and humans; the precise mechanisms of action remain unclear. In particular, there have been conflicting reports on the degree to which FGF21-induced weight loss in non-human primates is attributable to a decrease in food intake versus an increase in energy expenditure. Here, we present a semi-mechanistic mathematical model of energy balance and body composition developed from similar work in mice. This model links PF-05231023 administration and washout to changes in food intake, which in turn drives changes in body weight. The model is calibrated to and compared with recently published data from cynomolgus macaques treated with PF-05231023, demonstrating its accuracy in describing pharmacotherapy-induced weight loss in these animals. The results are consistent with the hypothesis that PF-05231023 decreases body weight in cynomolgus macaques solely by a reduction in food intake, with no direct effect on energy expenditure.
doi:10.1007/s10928-016-9481-1
PMCID: PMC4954843  PMID: 27405817
FGF21; Non-human primate; Body weight; Obesity; K-PD; Energy balance; Mathematical Model
45.  Impact of idiopathic pulmonary fibrosis on advanced non-small cell lung cancer survival 
Purpose
The clinical features of patients with advanced non-small cell lung cancer (NSCLC) and interstitial lung disease (ILD) have not fully been elucidated. This study aimed to investigate the clinical features of these patients, particularly with idiopathic pulmonary fibrosis (IPF).
Methods
Data on 218 patients with pathologically confirmed diagnoses of NSCLC who had been treated with chemotherapy and/or molecular targeted therapy were retrospectively analyzed for progression-free survival (PFS), overall survival (OS), responses to first-line therapy, and incidence of acute exacerbations (AEs).
Results
Fifty-three of the 218 patients were diagnosed with ILD, and 34 of them with IPF. The frequency of epidermal growth factor receptor (EGFR) mutation was significantly lower in ILD and IPF patients than in non-ILD patients (2 or 0 vs. 32 %, respectively). Median PFS and OS were significantly shorter in both ILD and IPF patients than in non-ILD patients (118, 92, and 196 days for PFS, and 267, 223, and 539 days for OS, respectively). Multivariate analysis showed that poor performance status, absence of EGFR mutation, and presence of IPF were poor prognostic factors for PFS and OS. Disease control rate (DCR) was significantly lower in ILD and IPF patients than in non-ILD patients regardless of the presence of EGFR mutation (67 or 53 vs. 85 %, respectively). The incidence of AEs of ILD was significantly higher during chemotherapy with docetaxel-containing regimens (seven of 38; 18.4 %).
Conclusions
Both IPF and ILD were associated with lower EGFR positivity, lower DCR, and shorter PFS and OS in advanced NSCLC patients.
doi:10.1007/s00432-016-2199-z
PMCID: PMC4954838  PMID: 27350261
Interstitial lung disease; Chemotherapy; Docetaxel; Acute exacerbation; Epidermal growth factor receptor; Advanced lung cancer
46.  Evidence of Factorial Validity of Parental Knowledge, Control and Solicitation, and Adolescent Disclosure Scales: When the Ordered Nature of Likert Scales Matters 
For evaluating monitoring and parent-adolescent communication, a set of scales addressing parental knowledge, control and solicitation, and adolescent disclosure was proposed by Kerr and Stattin (2000). Although these scales have been widely disseminated, their psychometric proprieties have often been found to be unsatisfactory, raising questions about their validity. The current study examines whether their poor psychometric properties, which are mainly attributed to the relatively poor conceptual quality of the items, could have been caused by the use of less-than-optimal analytical estimation methods. A cross-validation approach is used on a sample of 1071 adolescents. Maximum likelihood (ML) is compared with the diagonal weighted least squares (DWLS) method, which is suitable for Likert scales. The results of the DWLS approach lead to a more optimal fit than that obtained using ML estimation. The DWLS methodology may represent a useful option for researchers using these scales because it corrects for their unreliability.
doi:10.3389/fpsyg.2016.00941
PMCID: PMC4916221  PMID: 27445909
parental monitoring; adolescent disclosure; Likert scales; confirmatory factor analysis; diagonal weighted least squares
47.  Large-Conductance Calcium-Activated Potassium Channels in Glomerulus: From Cell Signal Integration to Disease 
Large-conductance calcium-activated potassium (BK) channels are currently considered as vital players in a variety of renal physiological processes. In podocytes, BK channels become active in response to stimuli that increase local cytosolic Ca2+, possibly secondary to activation of slit diaphragm TRPC6 channels by chemical or mechanical stimuli. Insulin increases filtration barrier permeability through mobilization of BK channels. In mesangial cells, BK channels co-expressed with β1 subunits act as a major component of the counteractive response to contraction in order to regulate glomerular filtration. This review aims to highlight recent discoveries on the localization, physiological and pathological roles of BK channels in glomerulus.
doi:10.3389/fphys.2016.00248
PMCID: PMC4915313  PMID: 27445840
BK channels; podocytes; mesangial cells; β subunits; glomerular filtration
48.  Elevated expression of Nodal and YAP1 is associated with poor prognosis of gastric adenocarcinoma 
Purpose
To investigate the correlation between Nodal and YAP1 expression and the clinicopathological characteristics of gastric adenocarcinoma (GAC).
Methods
Quantitative real-time RT-PCR, Western blot, and immunohistochemistry were performed to measure Nodal and YAP1 mRNA and protein in 20 fresh frozen samples and 220 paraffin-embedded GAC tissues with their paired non-tumor mucosa (PNTM). The prognostic values of Nodal and YAP1 were evaluated in 161 GAC patients using univariate and multivariate analyses.
Results
Both mRNA and protein expression of Nodal and YAP1 were significantly increased in GAC compared to PNTM (P < 0.05). Immunohistochemistry showed that Nodal was more highly expressed in 56.4 % GAC samples compared to PNTM; additionally, Nodal expression correlated with depth of tumor invasion, lymph node metastasis, and distant metastasis (all P < 0.05). There was no association between Nodal and YAP1 in GAC (P = 0.171). Kaplan–Meier analysis showed that the outcome of Nodal-high patients was significantly worse than those with low Nodal expression (χ2 = 30.452, P < 0.001). Cox multivariate regression showed that high Nodal expression was an independent risk factor affecting the prognosis of GAC patients (P = 0.000, RR = 2.976). Furthermore, patients with tumors in which both Nodal and YAP1 were expressed at high levels had the worst prognosis.
Conclusions
Elevated Nodal expression is a marker of poor prognosis in gastric cancer. Patient outcome is further worsened if Nodal and YAP1 are both expressed in the same tumor. The datas we present here suggest that the inhibition of Nodal signaling may represent a new therapeutic strategy for the treatment of gastric adenocarcinoma.
doi:10.1007/s00432-016-2188-2
PMCID: PMC4954832  PMID: 27325246
Nodal; YAP1; Gastric adenocarcinoma; Prognosis
49.  Analysis of peginterferon β-1a exposure and Gd-enhanced lesion or T2 lesion response in relapsing-remitting multiple sclerosis patients 
The effect of subcutaneous (SC) peginterferon β-1a exposure on reduction of gadolinium-enhanced (Gd+) lesion count over time was evaluated in patients with relapsing-remitting multiple sclerosis (RRMS) in a Phase 3 study (ADVANCE). Patients were randomized to receive SC injections of placebo (n = 500), 125 mcg every-2-weeks (n = 512), or 125 mcg every-4-weeks (n = 500) for 1 year, and then active treatment in the second year. Steady state 4-week AUC (AUCss) was derived for each individual based on sparse pharmacokinetic (PK) sample and a population PK model. Several longitudinal count models, including marginal, mixed effect, and mixture models, were compared to explore the relationship between AUCss and Gd+ lesion count (or T2 lesion count). A mixture model which divided subjects into two subpopulations by low and high baseline lesion activity was found to yield best goodness-of-fit for the data. In this model, the point estimate and 95 % CI for drug effect slope on log(λ) are −0.0256 (−0.0304, −0.0216) for Gd+ lesion and −0.0147 (−0.0170, −0.0124) for T2 lesion. This suggested that reduction of Gd+ lesion (or T2 lesion) count over time is significantly related to SC peginterferon β-1a exposure, and that the increased reduction lesion count with the every-2-week regimen versus the every-4-week regimen was driven by the higher exposure achieved in that treatment arm (mean Gd+ lesion count 0.2 and 0.7 at Year 2, respectively). The every-2-week regimen produced an exposure range that was close to the plateau range of the exposure–response curve, supporting its selection as the regulatory approved dosage.
Electronic supplementary material
The online version of this article (doi:10.1007/s10928-016-9477-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s10928-016-9477-x
PMCID: PMC4954841  PMID: 27299457
Peginterferon β-1a; Multiple sclerosis; Longitudinal count data; Mixture model; Population pharmacokinetics; Exposure–response
50.  Applying Public Health Screening Criteria: How Does Universal Newborn Screening Compare to Universal Tumor Screening for Lynch Syndrome in Adults with Colorectal Cancer? 
Journal of genetic counseling  2014;24(3):409-420.
Institutions have increasingly begun to adopt universal tumor screening (UTS) programs whereby tumors from all newly diagnosed patients with colorectal cancer (CRC) are screened to identify who should be offered germline testing for Lynch syndrome (the most common cause of hereditary CRC). Given limited information about the impact of universal screening programs to detect hereditary disease in adults, we apply criteria used to evaluate public health screening programs and compares and contrasts UTS with universal newborn screening (NBS) for the purpose of examining ethical implications and anticipating potential outcomes of UTS. Both UTS and a core set of NBS conditions clearly meet most of the Wilson and Jungner screening criteria. However, many state NBS panels include additional conditions that do not meet several of these criteria, and there is currently insufficient data to confirm that UTS meets some of these criteria. Comparing UTS and NBS with regard to newer screening criteria raises additional issues that require attention for both UTS and NBS. Comparisons also highlight the importance of evaluating the implementation of genomic tests to ensure or improve their effectiveness at reducing morbidity and mortality while minimizing potential harms.
doi:10.1007/s10897-014-9769-5
PMCID: PMC4402101  PMID: 25323653
Public Health Genomics; Lynch syndrome; Newborn Screening; Screening Criteria; Tumor screening

Results 26-50 (981)