bluuebunny/crossref_metadata_2025 huggingface dataset:
Nuclear localisation of 53BP1 is regulated by phosphorylation of the nuclear localisation signal
Authors: von Morgen Patrick , Lidak Tomas , Horejsi Zuzana , Macurek Libor
Published: March 2018

Background Information

Repair of damaged DNA is essential for maintaining genomic stability. TP53‐binding protein 1 (53BP1) plays an important role in repair of the DNA double‐strand breaks. Nuclear localisation of 53BP1 depends on importin β and nucleoporin 153, but the type and location of 53BP1 nuclear localisation signal (NLS) have yet to be determined.

Results

Here, we show that nuclear import of 53BP1 depends on two basic regions, namely 1667‐KRK‐1669 and 1681‐KRGRK‐1685, which are both needed for importin binding. Lysine 1667 is essential for interaction with importin and its substitution to arginine reduced nuclear localisation of 53BP1. Furthermore, we have found that CDK1‐dependent phosphorylation of 53BP1 at S1678 impairs importin binding during mitosis. Phosphorylation‐mimicking mutant S1678D showed reduced nuclear localisation, suggesting that phosphorylation of the NLS interferes with nuclear import of the 53BP1

Conclusions

We show that 53BP1 contains a classical bipartite NLS 1666‐GKRKLITSEEERSPAKRGRKS‐1686, which enables the importin‐mediated nuclear transport of 53BP1. Additionally, we found that posttranslational modification within the NLS region can regulate 53BP1 nuclear import.

Significance

Our results indicate that integrity of the NLS is important for 53BP1 nuclear localisation. Precise mapping of the NLS will facilitate further studies on the effect of posttranslational modifications and somatic mutations on the nuclear localisation 53BP1 and DNA repair.
Differential North Atlantic control of winter hydroclimate in late Holocene varved sediments of Lake Kortejärvi, eastern Finland
Authors: Czymzik Markus , Haltia Eeva , Saarni Saija , Saarinen Timo , Brauer Achim
Published: March 2018

Sediment microfacies, geochemical μ‐XRF and X‐ray density analyses were conducted on varved sediments from Lake Kortejärvi (eastern Finland) covering the last 2700 years. The varves comprise couplets of detrital and organic sub‐layers throughout the complete time‐span. Based on their microfacies and stratigraphical position within a varve as well as comparisons with local discharge and meteorological data, thicker detrital layers are interpreted to reflect intensified snow‐melt floods following more humid winters. Detailed comparisons with monthly to annually resolved North Atlantic Oscillation (NAO) indices back to AD 1049 (901 a BP) suggest that multidecadal increases in snow‐melt layer thickness tend to be connected with a more positive phase of the NAO and, consequently, warmer winters. In contrast, distinct centennial intervals of thicker snow‐melt layers from −40 to 170, 280 to 460 and 1900 to 2300 a BP as well as around 2600 a BP do not consistently correspond to a particular NAO phase, but coincide with extended sea‐ice margins and a colder North Atlantic climate, causing intensified and southward shifted westerly cyclones. Our results point to a differential modification of North Atlantic winter hydroclimate working on varying time scales.
Implications for conifer glacial refugia and postglacial climatic variation in western Beringia from lake sediments of the Upper Indigirka basin
Authors: Lozhkin Anatoly , Anderson Patricia , Minyuk Pavel , Korzun Julya , Brown Thomas , Pakhomov Alexander , Tsygankova Valeriya , Burnatny Sergei , Naumov Alexey
Published: March 2018

A c. 13 800 cal. a BP palynological record from Tschuch'ye Lake (eastern Yakutia), when combined with other palaeobotanical records from western Beringia, supports previous conclusions that Larix and Pinus pumila spread from multiple cryptic refugia during the Lateglacial period and middle Holocene, respectively. The antiquity and spatial distribution of Larix in many of these records suggest that full‐glacial landscapes probably had a small but important tree component. The Tschuch'ye record further indicates the absence of a Younger Dryas climatic reversal and is in accord with the preponderance of other data from western Beringia, which indicate warmer than present climates between c. 12 900 and 9100 cal. a BP. The subsequent spread of Pinus pumila, which has similar temperature requirements as Larix, denotes a shift to wetter but still warm climates during the middle Holocene, with palynological data suggesting optimal conditions in far western areas of western Beringia c. 7000–5000 cal. a BP. The postglacial occurrence of relatively warm/dry and warm/wet intervals is consistent with results of a regional climate‐model simulation that indicates warmer than present temperatures and decreased effective moisture at 11 000 cal. a BP and persistence of warm conditions but with greater moisture and longer growing season at 6000 cal. a BP.
Episodic fluid flow as a trigger for Miocene‐Pliocene slope instability on the Utgard High, Norwegian Sea
Authors: Omosanya Kamaldeen Olakunle
Published: March 2018

Mass wasting is triggered on many continental slopes by a number of mechanisms, including seismic shaking, high sedimentation rates, the presence of weak geological units and gas hydrate dissociation. In this study, the morphology of a Late Miocene–Early Pliocene mass‐transport complex (MTC) on the Utgard High is unravelled and discussed in relation to possible trigger mechanisms. The approach used here includes 3D seismic interpretation and the analysis of variance attribute maps. The interpreted MTC is located on the crest and flanks of the Utgard High and is composed of three mass‐transport deposits with seismic characters varying from transparent and chaotic seismic facies at the base to slightly deformed layers composed of mounds and rafted blocks in the middle and chaotic to transparent reflections at the top. Lithologically, the MTC consists predominantly of claystone with high gamma ray and low density and resistivity values, demonstrating that the associated mounds represent remobilized ooze sediments. A vertical stack of six magmatic sills emplaced from 55.6 to 56.3 Ma into the Upper Cretaceous shales is interpreted at depths of 3,000–5,500 ms two‐way travel time (TWTT). In association with these magmatic sills are several hydrothermal vent complexes that interacted with the top MTC horizon, signifying that episodic and secondary fluid‐venting events might be the principal mechanism facilitating mass wasting in the study area. In addition, the remobilization of ooze sediments into mounds is hypothesized to be dependent on fluids and clayey layers. As a corollary of this work, the importance of relict and recurrent episodes of fluid flow in the Vøring Basin and their influence on the geotechnical integrity of the overburden and later mass wasting is established.
Effects of litter size and quality on processing by decomposers in a tropical savannah stream
Authors: de Souza Rezende Renan , Leite Gustavo Figueiredo Marques , Ramos Kamilla , Torres Isabella , Tonin Alan M. , Gonçalves Júnior José Francisco
Published: March 2018

Litter fragment size and quality can have profound effects on ecosystem functioning and global biogeochemical cycling due to differential utilization by decomposers. Here we study the influence of these factors on decomposers from two guilds found in a tropical savannah stream: invertebrate shredders of the genus Phylloicus and microorganisms. Containers (16 × 16 × 12 cm, ~ 3L) with either Phylloicus (cases removed; N = 16) or stream water containing microorganisms (N = 16) were supplied with litter from the species Inga laurina, Maprounea guianensis, and Richeria grandis, and cut into disks of 18.7, 13.2, and 8.1 mm in diameter (3 sizes × 3 species = 9 disks per container). Relative decomposition was greater for smaller leaf disks and disks of higher quality in microbial‐only cultures. Phylloicus preferentially harvested large fragments for case building, also preferring the leaves of M. guianensis and R. grandis, likely due increased robustness for case formation. Microbial decomposition resulted in ~20% litter mass loss compared to 30% in Phylloicus (of which 8% was used for case building and 24% for food). Thus, changes to input litter size, such as a decrease in leaf size after drought, may alter microbial decomposition and potentially affect shredder populations by limiting the availability of casing material.
Seasonal flooding, topography, and organic debris interact to influence the emergence and distribution of seedlings in a tropical grassland
Authors: Bao Francielli , Elsey‐Quirk Tracy , de Assis Marco Antonio , Arruda Rafael , Pott Arnildo
Published: March 2018

In seasonally flooded wetlands, inundation and associated organic debris deposition followed by a drawdown period can promote plant community diversity across space and time. Post‐flood regeneration might be influenced by the direct effect of flooding on seed dispersal and seedling emergence, as well as the indirect effect of organic debris on seed trapping and germination. Our objective was to examine the influence of seasonal flooding, topography, and organic debris cover on seedling distribution in a seasonally flooded grassland. We measured species richness, seedling abundance, and organic debris cover for 3 yr in a seasonally flooded grassland in the Pantanal, Brazil, at three topographic levels at the end of the flood season and during the dry season when there was no debris deposition. A total of 43 species were recorded, with no difference in species richness detected between seasons. However, the abundance of some species was higher post‐flood than during the dry period. The greatest seedling abundance and richness were found post‐flood at intermediate elevations, followed by high and the lowest elevations. Seed germination and seedling establishment were likely suppressed at low topographic positions due to shading from organic debris and poor drainage. Therefore, areas with predictable annual floods promote diversity by creating spatial and temporal variations in environmental conditions.
Long non‐coding RNA‐CTD‐2108O9.1 represses breast cancer metastasis by influencing leukemia inhibitory factor receptor
Authors: Wang Mozhi , Wang Mengshen , Wang Zhenning , Yu Xueting , Song Yongxi , Wang Chong , Xu Yujie , Wei Fengheng , Zhao Yi , Xu Yingying
Published: March 2018

Breast cancer (BC) is an aggressive malignant disease in women worldwide with a high tendency to metastasize. However, important biomarkers for BC metastasis remain largely undefined. In the present study, we identified that long non‐coding RNA‐CTD‐2108O9.1 is downregulated in BC tissues and cells and acts as a metastatic inhibitor of BC. Mechanistic investigation determined that lncRNA‐CTD‐2108O9.1 represses metastasis by targeting leukemia inhibitory factor receptor (LIFR), which is designated as a metastasis suppressor in BC. Our study characterizes a significant tumor suppressor active in BC metastasis repression through the known metastasis inhibitor LIFR.
Antibacterial activity and in vivo wound healing potential of phenolic extracts from jaboticaba skin
Authors: Machado Gustavo Henrique Andrade , Marques Tamara Rezende , de Carvalho Thaís Cristina Lima , Duarte André Carvalho , de Oliveira Flávia Cíntia , Gonçalves Michelle Carlota , Piccoli Roberta Hilsdorf , Corrêa Angelita Duarte
Published: March 2018

In this study, different phenolic extracts were obtained from the jaboticaba skin meal (JSM), whose phenolic compounds were characterized and their antibacterial activities were assessed. Moreover, the activity of lyophilized ethanolic extract of jaboticaba skin (EEJS) on wound healing was analyzed in rats. TheJSMphenolic extracts were obtained in four ways: aqueous, methanolic, ethanolic, and acetone extracts. The phenolic compounds were characterized in these extracts by high‐performance liquid chromatography, and their antibacterial activities were evaluated. The in vivo experiment was divided into four groups and received the following treatments: G1—silver sulfadiazine (positive control); G2—EEJSat 10%; G3—EEJSat 5%, and G4—EEJSat 2.5%. The aqueous extract did not inhibit the growing of any bacterium. The ethanolic, acetone, and methanolic extracts inhibited the growing of all bacteria tested at the concentrations of 1.25%, 2.50%, and 5.00%, respectively. The ethanolic extract was the one that showed the highest bacterial inhibition potential and the highest contents of phenolic compounds, especially of catechin, epicatechin gallate, and epicatechin. The G3 and G4 treatments presented faster wound healing compared to the G1 one, as it promoted a less intense inflammatory reaction and full closure of the wounds at an accelerated rate.
Response Time Adjustment in the Stop Signal Task: Development in Children and Adolescents
Authors: Dupuis Annie , Indralingam Maheshan , Chevrier Andre , Crosbie Jennifer , Arnold Paul , Burton Christie L. , Schachar Russell
Published: March 2018

Adjusting speed to maintain fast and accurate performance is critical to goal‐directed behavior. This study examined development of response time adjustments in the stop signal task in 13,709 individuals aged 6–17 years (49.0% Caucasian) across four trial types: correct and incorrect go, successful (stop‐inhibit), and failed (stop‐respond) trials. People sped more after correct than incorrect go responses and slowed more after failed than successful stop trials. Greater slowing after stop‐respond but less slowing after stop‐inhibit trials was associated with better response inhibition. Response time adjustments were evident in children as young as age 6, developed throughout childhood, and plateaued by age 10. Results were consistent with the predictions of the error detection and shifting goal priority hypotheses for adjustments.
Remodelling and inflammation in preschoolers with severe recurrent wheeze and asthma outcome at school age
Authors: Lezmi G. , Deschildre A. , Abou Taam R. , Fayon M. , Blanchon S. , Troussier F. , Mallinger P. , Mahut B. , Gosset P. , de Blic J.
Published: March 2018

Background

The influence of airway remodelling and inflammation in preschoolers with severe recurrent wheeze on asthma outcomes is poorly understood.

Objective

To assess their association with asthma symptoms and lung function at school age.

Methods

Preschoolers (38.4 months) initially investigated with bronchial biopsies were re‐assessed for asthma symptoms and lung function at school age.

Results

Thirty‐six of 49 preschoolers (73.5%) were assessed at 10.9 years. Twenty‐six (72.2%) had persistent asthma. Submucosal eosinophil counts were higher in children with severe exacerbations at school age than in those without (16/0.1 mm2 [11.2‐30.4] vs 8/0.1 mm2 [2.4‐17.6], P = .02), and correlated with the number of severe exacerbations (P = .04, r = .35). Submucosal neutrophil counts correlated with FEV1/FVC (P < .01, r = .47) and FEF25‐75% predicted (P = .02, r = .43). Airway smooth muscle (ASM) area correlated with FEV1/FVC (P < .01, r = .51). Vessel numbers negatively correlated with FEV1% predicted and FEV1/FVC (P = .03, r = −.42; P = .04, r = −.41; respectively) and FEF25‐75% predicted (P = .02, r = −.46).

Conclusion

Eosinophilic inflammation in preschoolers with severe recurrent wheeze might be predictive of future severe exacerbations, neutrophilia might be associated with better lung function. Changes in ASM and vascularity might affect lung function at school age.
PR-957 mediates neuroprotection by inhibiting Th17 differentiation and modulating cytokine production in a mouse model of ischaemic stroke
Authors: Guo Y , Chen X , Li D , Liu H , Ding Y , Han R , Shi Y , Ma X
Published: March 2018

Acute ischaemic stroke can induce secondary brain injury by activating an inflammatory response that contributes to clinical impairment. As a specific inhibitor of the immunoproteasome subunit low molecular weight polypeptide 7 (LMP7), PR-957 may participate in regulating pathophysiological and inflammatory responses in multiple diseases of the central nervous system (CNS). We investigated the neuroprotective properties of PR-957 in a mouse model of stroke, induced by middle cerebral artery occlusion (MCAO). After MCAO and injections of PR-957 or vehicle, we evaluated mice behaviourally using modified Neurological Severity Scores (mNSS) and sensorimotor tests, including the adhesive-removal test, a foot-fault test and an inclined plane test. Infarct volume was measured 24 and 72 h after MCAO. Infiltration by different lymphocyte subpopulations was evaluated by flow cytometry and immunofluorescent staining of brain tissue from the penumbral area. Quantitative real-time polymerase chain reaction analysis and enzyme-linked immunosorbent assay were used to measure the expression of proinflammatory cytokines: interkeukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL-17A, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, granulocyte colony-stimulating factor (GCSF) and granulocyte–macrophage colony-stimulating factor (GM-CSF). Expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT-3) protein levels in brain was measured by immunoblot. MCAO mice treated with PR-957 showed a significant decrease in infarct volume and had mild neurological deficits compared to vehicle-treated mice. PR-957 administration also significantly decreased IL-1β, IL-6, IL-12, IL-17A and TNF-α. PR-957 provides neuroprotection via inhibiting T lymphocyte infiltration and decreasing T helper type 17 (Th17) cell differentiation in MCAO mice, which may result from the reduced expression of pSTAT-3. The neuroprotective effect of PR-957 indicates its potential utility as anti-inflammatory therapy for ischaemic stroke.
Association of interleukin 22 gene polymorphisms and serum IL-22 level with risk of systemic lupus erythematosus in a Chinese population
Authors: Wang R , Zeng Y-L , Qin H-M , Lu Y-L , Huang H-T , Lei M , Tan T , Huang Y-Y , Luo H-C , Lan Y , Wei Y-S
Published: March 2018

The aim of this study was to investigate the association between the single-nucleotide polymorphisms (SNPs) of the interleukin 22 (IL-22) gene and systemic lupus erythematosus (SLE) in a Chinese population. Three IL-22 SNPs (rs2227485, rs2227513 and rs2227491) were genotyped using SNaPshot SNP genotyping assays and identified by sequencing in 314 SLE patients and 411 healthy controls. The IL-22 level of serum was assessed by enzyme-linked immunosorbent assay (ELISA) kits. Data were analysed by spss version 17.0 software. We found that rs2227513 was associated with an increased risk of SLE [AG versus AA: adjusted odds ratio (aOR) = 2·24, 95% confidence interval (CI) = 1·22–4·12, P = 0·010; G versus· A: adjusted OR = 2·18, 95% CI = 1·20-3·97, P = 0·011]. Further analysis in patients with SLE showed that the AG genotype and G allele were associated with an increased risk of renal disorder in SLE (G versus A: aOR = 3·09, 95% CI = 1·30–7·33, P = 0·011; AG versus· AA: aOR = 3·25, 95% CI = 1·35–7·85, P = 0·009). In addition, the concentration of IL-22 was significantly lower in the rs2227513 AG genotype compared with AA genotype (P = 0·028). These results suggest that rs2227513 polymorphism might contribute to SLE susceptibility, probably by decreasing the expression of IL-22.
Functional visceral fat activity evaluated by preoperative F‐18 FDG PET/CT predicts regional lymph node metastasis in differentiated thyroid cancer
Authors: Pahk Kisoo , Choi Sunju , Kim Sungeun
Published: March 2018

Objective

We investigated the predictive role of functional visceral fat activity evaluated by preoperative F‐18 FDG PET/CT for regional lymph node metastasis in patients with differentiated thyroid cancer.

Design and patients

Fifty‐eight patients with newly diagnosed differentiated thyroid cancer were enrolled in this study, retrospectively (men 14; women 44; age 53 ± 14.5). They all received preoperative F‐18 FDG PET/CT and surgery. Functional visceral fat activity was defined as maximum standardized uptake value (SUVmax) of visceral fat divided by SUVmax of subcutaneous fat (V/S ratio). Pathology results were confirmed through the surgical specimens.

Results

The patients with regional lymph node metastasis showed higher functional visceral fat activity (V/S ratio) than the patients without regional lymph node metastasis (2.12 ± 0.6 vs 1.62 ± 0.34, P = .001). V/S ratio of 1.78 was suggested as an optimal cut‐off value for predicting regional lymph node metastasis (sensitivity; 70.3%, specificity; 83.3%, area under the curve; 0.778, P < .0001). Furthermore, functional visceral fat activity was significantly associated with regional lymph node metastasis in patients with differentiated thyroid cancer by univariate and multivariate analyses.

Conclusions

Functional visceral fat activity significantly affects the regional lymph node metastasis status in patients with differentiated thyroid cancer. Furthermore, it may also be useful to predict regional lymph node metastasis.
Serum thyroid‐stimulating hormone levels and smoking status: Data from the Korean National Health and Nutrition Examination Survey VI
Authors: Park Suyeon , Kim Won Gu , Jeon Min Ji , Kim Mijin , Oh Hye‐Seon , Han Minkyu , Kim Tae Yong , Shong Young Kee , Kim Won Bae
Published: March 2018

Objective

We aimed to evaluate differences in serum thyroid‐stimulating hormone (TSH) levels according to smoking status and urine iodine concentration (UIC) in a healthy Korean population using data from the Sixth Korean National Health and Nutrition Examination Survey (KNHANES VI).

Study design

Sixth Korean National Health and Nutrition Examination Survey (2013‐2015) is a nationwide, cross‐sectional survey of the Korean population.

Patients

Research subjects were selected by two‐stage stratified cluster sampling of the population and housing census data. A total of 5639 subjects aged >18 years, who were not pregnant, and had undergone thyroid function testing during the survey period, were included.

Measurement

The level of serum TSH according to smoking status, iodine intake and presence of TPOAb were evaluated.

Results

In the reference population, mean serum TSH level in current smokers (1.87 mIU/L, 95% CI, 0.52‐5.37 mIU/L) was significantly lower than that in nonsmokers (2.33 mIU/L, 95% CI, 0.79‐6.69 mIU/L, P < .001). The rate of thyroperoxidase antibody (TPOAb) positivity was higher in never smoker (7.7%) than past smokers (5.1%) and current smokers (4.7%), but sex‐specific rate of TPOAb was not different according to smoking status. The lower serum TSH levels in current smokers were more apparent in iodine‐deficient subjects (UIC < 100 μg/L), and this change was diminished in subjects with UICs between 100 and 299 μg/L. The difference in serum TSH levels in current smokers disappeared in subjects with UICs ≥ 300 μg/L.

Conclusions

Smoking is associated with a left‐shift in serum TSH level that is more apparent in iodine‐deficient subjects. Smoking status is not associated with the presence of TPOAb or iodine intake. The results suggest that smoking has a direct effect on thyroid function that is not mediated by autoimmune processes in the thyroid gland.
Impact of timing on soft tissue augmentation during implant treatment: A systematic review and meta‐analysis
Authors: Lin Cho‐Ying , Chen Zhaozhao , Pan Whei‐Lin , Wang Hom‐Lay
Published: March 2018

Background

To achieve a predictable esthetic and functional outcome, soft tissue augmentation has become popular in implant treatment.

Objectives

The aim of this systematic review and meta‐analysis was to assess the influence of different timing for soft tissue augmentation during implant treatment on soft tissue conditions and its stability.

Material and methods

Electronic and manual searches for articles written in English up to September 2017 were performed by two independent reviewers. Human clinical studies with the purpose of evaluating outcomes (at least 3‐month follow‐up) of autogenous soft tissue graft for augmentation during implant treatment, either simultaneous or after implant placement (staged), were included. Cumulative changes of keratinized tissue width (KTW), soft tissue thickness (STT), and mid‐buccal mucosal recession (MR) data were analyzed with a random‐effects model to compare the postoperative outcomes.

Results

Twenty‐nine human studies (eight randomized clinical trials, six cohort studies, and 15 case series) that met the inclusion criteria were included. For the overall data, the weighted mean STT gain (1 year after surgery) was 1.03 mm (95% CI: 0.78–1.29 mm), among which the simultaneous group was 1.12 mm (95% CI: 0.75–1.49 mm) and staged group (3–6 months after implant placement) was 0.95 mm (95% CI: 0.58–1.31 mm). There was no statistically significant difference in KTW and MR between 3 months and more than 3 months after surgery.

Conclusions

This review revealed that the stability of soft tissue, in terms of KTW and mid‐buccal MR, can be obtained 3 months after surgery. There is no difference between simultaneous and staged soft tissue augmentation during implant treatment, and both procedures significantly enhance KTW and STT.
Revisiting the promise of conservation psychology
Authors: Selinske Matthew J. , Garrard Georgia E. , Bekessy Sarah A. , Gordon Ascelin , Kusmanoff Alexander M. , Fidler Fiona
Published: March 2018

Article impact statement: Continued development of conservation psychology is essential to addressing the challenges of biodiversity conservation.
Restorative surgery after colectomy for ulcerative colitis in England and Sweden: observations from a comparison of nationwide cohorts
Authors: Worley G. , Nordenvall C. , Askari A. , Pinkney T. , Burns E. , Akbar A. , Olén O. , Ekbom A. , Bottai M. , Myrelid P. , Faiz O.
Published: March 2018

Aim

A longstanding disparity exists between the approaches to restorative surgery after colectomy for patients with ulcerative colitis (UC) in England and Sweden. This study aims to compare rates of colectomy and restorative surgery in comparable national cohorts.

Method

The English Hospital Episode Statistics (HES) and Swedish National Patient Register (NPR) were interrogated between 2002 and April 2012. Patients with two diagnostic episodes for UC (age ≥ 15 years) were included. Patients were excluded if they had an episode of inflammatory bowel disease or colectomy before 2002. The cumulative incidences of colectomy and restorative surgery were calculated using the Kaplan–Meier method.

Results

A total of 98 691 patients were included in the study, 76 129 in England and 22 562 in Sweden. The 5‐year cumulative incidence of all restorative surgery after colectomy in England was 33% vs 46% in Sweden (P‐value < 0.001). Of the patients undergoing restorative surgery, 92.3% of English patients had a pouch vs 38.8% in Sweden and 7.7% vs 59.1% respectively had an ileorectal anastomosis (IRA). The 5‐year cumulative incidence of colectomy in this study cohort was 13% in England and 6% in Sweden (P‐value < 0.001).

Conclusion

Following colectomy for UC only one‐third of English patients and half of Swedish patients underwent restorative surgery. In England nearly all these patients underwent pouches, in Sweden a less significant majority underwent IRAs. It is surprising to demonstrate this discrepancy in a comparable cohort of patients from similar healthcare systems. The causes and consequences of this international variation in management are not fully understood and require further investigation.
Decreased risk for microscopic colitis and inflammatory bowel disease among patients with reflux disease
Authors: Sonnenberg A. , Turner K. O. , Genta R. M.
Published: March 2018

Aim

Previous studies have found an increased risk for microscopic colitis (MC) associated with proton pump inhibitors. In patients with ulcerative colitis (UC) or Crohn's disease (CD), proton pump inhibitors have been associated with an increased risk for IBD flares and impaired outcomes. The aim of this study was to test the epidemiological associations between gastro‐oesophageal reflux disease (GERD) and MC, UC or CD in a large database.

Method

The Miraca Life Sciences Database is a national electronic repository of histopathological records of patients distributed throughout the entire USA. A case–control study evaluated whether the presence of Barrett's metaplasia, erosive oesophagitis on endoscopy or histological signs of reflux oesophagitis, clinical diagnosis of GERD or any GERD type affected the occurrence of MC, UC or CD among 228 506 subjects undergoing bidirectional endoscopy. Multivariate logistic regression analyses were used to calculate ORs and their 95% CI for the risk of MC, UC or CD associated with various types of GERD and were adjusted for age, sex and presence of Helicobacter pylori.

Results

The analysis revealed an inverse relationship between GERD and different types of inflammatory bowel disease. The inverse relationships applied similarly to MC (mean = 0.62, 95% CI: 0.58–0.66), UC (mean = 0.89, 95% CI: 0.81–0.97) and CD (mean = 0.76, 95% CI: 0.69–0.85). It also applied to different forms of GERD, with a trend towards more pronounced inverse relationships associated with Barrett's metaplasia or erosive oesophagitis than clinical diagnosis of GERD.

Conclusion

Gastro‐oesophageal reflux disease is inversely associated with all forms of inflammatory bowel disease, such as MC, UC, or CD.
HOW EFFECTIVE ARE EXPERT TV HOSTS AT SAVING FAILING BUSINESSES?
Authors: Sobel Russell S. , Sobel Reagan N. , Walker Douglas M. , Calcagno Peter T.
Published: March 2018

The profit and loss system is an integral part of a dynamic market economy. Losses eliminate businesses that are inefficiently managed or whose products no longer provide sufficient value. Almost a dozen popular television shows feature entertaining expert hosts claiming to “save” failing businesses with injections of physical and human capital. We undertake the first comprehensive analysis of these shows, calculating the failure rates of the businesses and analyzing the incentive structure facing the shows, networks, hosts, and participants. In general, we find that these shows are largely unsuccessful in saving failing businesses. (JEL L26, L82)
Overstating the value of the IUCN Red List for business decision‐making
Authors: Burgass Michael J. , Arlidge William N.S. , Addison Prue F.E.
Published: March 2018

The relationship between business and conservation is growing increasingly closer, with the recognition that collaboration can lead to better outcomes for biodiversity. Bennun et al. introduce the IUCN Red List of Threatened Species (the Red List) to inform businesses' mitigation of biodiversity impacts; and subsequently how it can be improved to further increase its effectiveness. While we applaud this ever‐closer union of business and conservation, we believe the authors overinflate the value of the Red List in decision‐making, do not account for its limitations and therefore do not justify their conclusions for improving the Red List for business use. We are concerned this focus on wide application of the Red List promotes it as a “one‐stop‐shop” and could lead to discounting of more appropriate approaches.
Durability of the hepatitis B vaccination in pediatric renal transplant recipients
Authors: Miller‐Handley Hilary , Paulsen Grant , Hooper David K. , Lake Michael , Lazear Danielle , Danziger‐Isakov Lara
Published: March 2018

Since hepatitis B virus (HBV) vaccine implementation, HBV infection has significantly decreased. However, adult renal transplant recipients show a higher rate of seroreversion compared to the general population, leading to HBV infection risk. Data are limited in pediatric renal transplant recipients. Retrospective data were collected to determine the seroprotection and durability of HBV vaccination in pediatric renal transplant patients from 2004 to 2014. One hundred subjects were categorized based on pre‐ and post‐transplant hepatitis B surface antibody (HBsAb). Pretransplant, 85 recipients (85%) had a positive HBsAb compared to 15 (15%) with negative HBsAb. In univariable analyses, other than age (P < .05) no significant differences existed pretransplant by demographics, pretransplantation dialysis, or number of vaccinations. Of the 85 pretransplantation responders, 53 (62%) remained HBsAb positive post‐transplantation, 28 (32%) seroreverted, and 4 developed indeterminate titers. All seroreversions occurred within 5 years post‐transplant. Receipt of a living donor organ had higher risk of reversion (P = .005). No significant differences were found in demographics, pretransplantation dialysis, vaccination number, or acute rejection. Despite vaccination, 15% of pediatric renal transplant candidates were seronegative, and an additional 32% lost seroprotection within 5 years post‐transplantation leaving nearly half of transplant recipients at risk for HBV infection.
A Translational Model of Incomplete Catch‐Up Growth: Early‐Life Hypoxia and the Effect of Physical Activity
Authors: Radom‐Aizik Shlomit , Zaldivar Frank P. , Nance Dwight M. , Haddad Fadia , Cooper Dan M. , Adams Gregory R.
Published: March 2018

Advances in therapies have led to prolonged survival from many previously lethal health threats in children, notably among prematurely born babies and those with congenital heart disease. Evidence for catch‐up growth is common in these children, but in many cases the adult phenotype is never achieved. A translational animal model is required in which specific tissues can be studied over a reasonable time interval. We investigated the impact of postnatal hypoxia (HY) (12%O2 (HY12) or 10% O2 (HY10)) on growth in rats relative to animals raised in room air. Subgroups had access to running wheels following the HY period. Growth was fully compensated in adult HY12 rats but not HY10 rats. The results of this study indicate that neonatal hypoxia can be a useful model for the elucidation of mechanisms that mediate successful catch‐up growth following neonatal insults and identify the critical factors that prevent successful catch‐up growth.
Can Graphics Tell Lies? A Tutorial on How To Visualize Your Data
Authors: Cabanski Christopher , Gilbert Houston , Mosesova Sofia
Published: March 2018

Visualizations are a powerful tool for telling a story about a data set or analysis. If done correctly, visualizations not only display data but also help the audience digest key information. However, if done haphazardly, visualization has the potential to confuse the audience and, in the most extreme circumstances, deceive. In this tutorial, we provide a set of general principles for creating informative visualizations that tell a complete and accurate story of the data.
Complexities of perceived and actual performance in pathology interpretation: A comparison of cutaneous melanocytic skin and breast interpretations
Authors: Carney Patricia A. , Frederick Paul D. , Reisch Lisa M. , Titus Linda , Knezevich Stevan R. , Weinstock Martin A. , Piepkorn Michael W. , Barnhill Raymond L. , Elder David E. , Weaver Donald L. , Elmore Joann G.
Published: March 2018

Background

Little is known about how pathologists process differences between actual and perceived interpretations.

Objective

To compare perceived and actual diagnostic agreement before and after educational interventions.

Methods

Pathologists interpreted test sets of skin and/or breast specimens that included benign, atypical, in situ and invasive lesions. Interventions involved self‐directed learning, one skin and one breast, that showed pathologists how their interpretations compared to a reference diagnoses. Prior to the educational intervention, participants estimated how their interpretations would compare to the reference diagnoses. After the intervention, participants estimated their overall agreement with the reference diagnoses. Perceived and actual agreements were compared.

Results

For pathologists interpreting skin, mean actual agreement was 52.4% and overall pre‐ and postinterventional mean perceived agreement was 72.9% vs 54.2%, an overestimated mean difference of 20.5% (95% confidence interval [CI] 17.2% to 24.0%) and 1.8% (95% CI −0.5% to 4.1%), respectively. For pathologists interpreting breast, mean actual agreement was 75.9% and overall pre‐ and postinterventional mean perceived agreement was 81.4% vs 76.9%, an overestimation of 5.5% (95% CI 3.0% to 8.0%) and 1.0% (95% CI 0.0% to 2.0%), respectively.

Conclusions

Pathologists interpreting breast tissue had improved comprehension of their performance after the intervention compared to pathologists interpreting skin lesions.
Validation study for development of the Japan NBI Expert Team classification of colorectal lesions
Authors: Iwatate Mineo , Sano Yasushi , Tanaka Shinji , Kudo Shin‐ei , Saito Shoichi , Matsuda Takahisa , Wada Yoshiki , Fujii Takahiro , Ikematsu Hiroaki , Uraoka Toshio , Kobayashi Nozomu , Nakamura Hisashi , Hotta Kinichi , Horimatsu Takahiro , Sakamoto Naoto , Fu Kuang‐I , Tsuruta Osamu , Kawano Hiroshi , Kashida Hiroshi , Takeuchi Yoji , Machida Hirohisa , Kusaka Toshihiro , Yoshida Naohisa , Hirata Ichiro , Terai Takeshi , Yamano Hiro‐o , Nakajima Takeshi , Sakamoto Taku , Yamaguchi Yuichiro , Tamai Naoto , Nakano Naoko , Hayashi Nana , Oka Shiro , Ishikawa Hideki , Murakami Yoshitaka , Yoshida Shigeaki , Saito Yutaka ,   The Japan NBI Expert Team (JNET)
Published: March 2018

Background and Aim

The Japan narrow‐band imaging (NBI) Expert Team (JNET) was organized to unify four previous magnifying NBI classifications (the Sano, Hiroshima, Showa, and Jikei classifications). The JNET working group created criteria (referred to as the NBI scale) for evaluation of vessel pattern (VP) and surface pattern (SP). We conducted a multicenter validation study of the NBI scale to develop the JNET classification of colorectal lesions.

Methods

Twenty‐five expert JNET colonoscopists read 100 still NBI images with and without magnification on the web to evaluate the NBI findings and necessity of the each criterion for the final diagnosis.

Results

Surface pattern in magnifying NBI images was necessary for diagnosis of polyps in more than 60% of cases, whereas VP was required in around 90%. Univariate/multivariate analysis of candidate findings in the NBI scale identified three for type 2B (variable caliber of vessels, irregular distribution of vessels, and irregular or obscure surface pattern), and three for type 3 (loose vessel area, interruption of thick vessel, and amorphous areas of surface pattern). Evaluation of the diagnostic performance for these three findings in combination showed that the sensitivity for types 2B and 3 was highest (44.9% and 54.7%, respectively), and that the specificity for type 3 was acceptable (97.4%) when any one of the three findings was evident. We found that the macroscopic type (polypoid or non‐polypoid) had a minor influence on the key diagnostic performance for types 2B and 3.

Conclusion

Based on the present data, we reached a consensus for developing the JNET classification.
Novel Pompe disease phenotype: a treatment‐related modified phenotype neglecting the brain
Authors: Schoser Benedikt
Published: March 2018

This commentary is on the original article by Ebbink et al. on pages 579–586 of this issue.
Towards more accurate prognostication after preterm birth
Authors: Morgan Catherine
Published: March 2018

This commentary is on the original article by Peyton et al. on pages 1239–1243 of this issue.
Continuous glucose monitoring during diabetic pregnancy (GlucoMOMS): A multicentre randomized controlled trial
Authors: Voormolen Daphne N. , DeVries J. Hans , Sanson Rieneke M. E. , Heringa Martijn P. , de Valk Harold W. , Kok Marjolein , van Loon Aren J. , Hoogenberg Klaas , Bekedam Dick J. , Brouwer Teri C. B. , Porath Martina , Erdtsieck Ronald J. , NijBijvank Bas , Kip Huib , van der Heijden Olivier W. H. , Elving Lammy D. , Hermsen Brenda B. , Potter van Loon B. J. , Rijnders Robert J. P. , Jansen Henry J. , Langenveld Josje , Akerboom Bettina M. C. , Kiewiet Rosalie M. , Naaktgeboren Christiana A. , Mol Ben W. J. , Franx Arie , Evers Inge M.
Published: March 2018

Aim

Diabetes is associated with a high risk of adverse pregnancy outcomes. Optimal glycaemic control is fundamental and is traditionally monitored with self‐measured glucose profiles and periodic HbA1c measurements. We investigated the effectiveness of additional use of retrospective continuous glucose monitoring (CGM) in diabetic pregnancies.

Material and methods

We performed a nationwide multicentre, open label, randomized, controlled trial to study pregnant women with type 1 or type 2 diabetes who were undergoing insulin therapy at gestational age < 16 weeks, or women who were undergoing insulin treatment for gestational diabetes at gestational age < 30 weeks. Women were randomly allocated (1:1) to intermittent use of retrospective CGM or to standard treatment. Glycaemic control was assessed by CGM for 5‐7 days every 6 weeks in the CGM group, while self‐monitoring of blood glucose and HbA1c measurements were applied in both groups. Primary outcome was macrosomia, defined as birth weight above the 90th percentile. Secondary outcomes were glycaemic control and maternal and neonatal complications.

Results

Between July 2011 and September 2015, we randomized 300 pregnant women with type 1 (n = 109), type 2 (n = 82) or with gestational (n = 109) diabetes to either CGM (n = 147) or standard treatment (n = 153). The incidence of macrosomia was 31.0% in the CGM group and 28.4% in the standard treatment group (relative risk [RR], 1.06; 95% CI, 0.83‐1.37). HbA1c levels were similar between treatment groups.

Conclusions

In diabetic pregnancy, use of intermittent retrospective CGM did not reduce the risk of macrosomia. CGM provides detailed information concerning glycaemic fluctuations but, as a treatment strategy, does not translate into improved pregnancy outcome.
Use of the waist‐to‐height ratio to predict cardiovascular risk in patients with diabetes: Results from the ADVANCE‐ON study
Authors: Rådholm Karin , Chalmers John , Ohkuma Toshiaki , Peters Sanne , Poulter Neil , Hamet Pavel , Harrap Stephen , Woodward Mark
Published: March 2018

Aims

Patients with type 2 diabetes have a high risk of cardiovascular disease (CVD). Central obesity has been particularly associated with this risk relationship. We aimed to evaluate waist to height ratio (WHtR) as a predictor of risk in such patients.

Methods

WHtR was evaluated as a predictor of the risk of CVD and mortality amongst 11 125 participants with type 2 diabetes in the ADVANCE and ADVANCE‐ON studies, and was compared with body mass index (BMI), waist circumference and waist hip ratio (WHR). Primary outcome was a composite of death from CVD, non‐fatal myocardial infarction or non‐fatal stroke. Secondary outcomes were myocardial infarction, stroke, cardiovascular death and death from any cause. Cox models were used, with bootstrapping to compare associations between anthropometric measures for the primary outcome.

Results

Median follow‐up time was 9.0 years. There was a positive association between WHtR and adverse outcomes. The hazard ratio (HR) (confidence interval), per SD higher WHtR, was 1.16 (1.11‐1.22) for the primary endpoint, with no heterogeneity by sex or region, but a stronger effect in individuals aged 66 years or older. The other 3 anthropometric measurements showed similar associations, although there was evidence that WHtR marginally outperformed BMI and WHR. Based on commonly used BMI cut‐points, the equivalent WHtR cut‐points were estimated to be 0.55 and 0.6, with no evidence of a difference across subgroups.

Conclusions

In patients with diabetes, WHtR is a useful indicator of future adverse risk, with similar effects in different population subgroups.
Determining the optimal dose of atrasentan by evaluating the exposure‐response relationships of albuminuria and bodyweight
Authors: Koomen Jeroen V. , Stevens Jasper , Mostafa Nael M. , Parving Hans‐Henrik , de Zeeuw Dick , Heerspink Hiddo J. L.
Published: March 2018

This study aimed to identify the optimal dose of the endothelin‐1 receptor antagonist atrasentan with maximal albuminuria reduction and minimal signs of sodium retention, as manifested by increase in bodyweight. Data from the RADAR‐JAPAN studies were used, evaluating the effect of 0.75 or 1.25 mg/d of atrasentan in 161 patients with type 2 diabetes and kidney disease. Individual pharmacokinetic parameters were estimated using a population pharmacokinetic approach. Subsequently, changes in the urinary albumin‐to‐creatinine ratio (UACR) and bodyweight from baseline after 2 weeks' exposure were modelled as a function of the pharmacokinetic parameters. The 0.75 and 1.25 mg doses showed a mean UACR reduction of 34.0% and 40.1%, whereas mean bodyweight increased by 0.9 and 1.1 kg, respectively. A large variation between individuals was observed in the UACR and bodyweight responses. Individual pharmacokinetic parameters correlated significantly with both individual UACR and bodyweight responses (P < .01). The individual response curves for UACR and bodyweight crossed at approximately the mean trough concentration of 0.75 mg atrasentan, indicating that 0.75 mg/d of atrasentan is the optimal dose for kidney protection with maximal efficacy (albuminuria reduction) and safety (minimal sodium retention).
Filling the gap between chemical carcinogenesis and the hallmarks of cancer: A temporal perspective
Authors: Demetriou Christiana A. , Degli Esposti Davide , Pullen Fedinick Kristi , Russo Federica , Robinson Oliver , Vineis Paolo
Published: March 2018

Background

Cancer is believed to arise through the perturbation of pathways and the order of pathway perturbation events can enhance understanding and evaluation of carcinogenicity. This order has not been examined so far, and this study aimed to fill this gap by attempting to gather evidence on the potential temporal sequence of events in carcinogenesis.

Design

The methodology followed was to discuss first the temporal sequence of hallmarks of cancer from the point of view of pathological specimens of cancer (essentially branched mutations) and then to consider the hallmarks of cancer that one well‐known carcinogen, benzo(a)pyrene, can modify.

Results

Even though the sequential order of driving genetic alterations can vary between and within tumours, the main cancer pathways affected are almost ubiquitous and follow a generally common sequence: resisting cell death, insensitivity to antigrowth signals, sustained proliferation, deregulated energetics, replicative immortality and activation of invasion and metastasis. The first 3 hallmarks can be regarded as almost simultaneous while angiogenesis and avoiding immune destruction are perhaps the only hallmarks with a varying position in the above sequence.

Conclusions

Our review of hallmarks of cancer and their temporal sequence, based on mutational spectra in biopsies from different cancer sites, allowed us to propose a hypothetical temporal sequence of the hallmarks. This sequence can add molecular support to the evaluation of an agent as a carcinogen as it can be used as a conceptual framework for organising and evaluating the strength of existing evidence.