bluuebunny/crossref_metadata_2025 huggingface dataset:
Maintaining a Reputation for Consistently Beating Earnings Expectations and the Slippery Slope to Earnings Manipulation
Authors: Chu Jenny , Dechow Patricia M. , Hui Kai Wai , Wang Annika Yu
Published: March 2019

This paper investigates whether maintaining a reputation for consistently beating analysts' earnings expectations can motivate executives to move from “within GAAP” earnings management to “outside of GAAP” earnings manipulation. We analyze firms subject to SEC enforcement actions and find that these firms consistently beat analysts' quarterly earnings forecasts in the three years prior to the manipulation period and continue to do so by smaller “beats” during the manipulation period. We find that manipulating firms beat expectations around 86 percent of the time in the 12 quarters prior to the manipulation period (versus 75 percent for control firms) and that manipulation often ends with a miss in expectations. We document that executives of manipulating firms face strong stock market and CEO pressure to perform. Prior to the manipulation period, these firms have high analyst optimism, growing institutional interest, and high market valuations, along with powerful CEOs. Further, we find that maintaining a reputation for beating expectations is more important than CEO overconfidence and is incremental to CEO equity incentives for explaining manipulation. Our results suggest that pressure to maintain a reputation for beating analysts' expectations can encourage aggressive accounting and, ultimately, earnings manipulation.
A quantitative framework for investigating the reliability of empirical network construction
Authors: Cirtwill Alyssa R. , Eklöf Anna , Roslin Tomas , Wootton Kate , Gravel Dominique
Published: March 2019

Descriptions of ecological networks typically assume that the same interspecific interactions occur each time a community is observed. This contrasts with the known stochasticity of ecological communities: community composition, species abundances and link structure all vary in space and time. Moreover, finite sampling generates variation in the set of interactions actually observed. For interactions that have not been observed, most datasets will not contain enough information for the ecologist to be confident that unobserved interactions truly did not occur.

Here, we develop the conceptual and analytical tools needed to capture uncertainty in the estimation of pairwise interactions. To define the problem, we identify the different contributions to the uncertainty of an interaction. We then outline a framework to quantify the uncertainty around each interaction by combining data on observed co‐occurrences with prior knowledge. We illustrate this framework using perhaps the most extensively sampled network to date.

We found significant uncertainty in estimates for the probability of most pairwise interactions. This uncertainty can, however, be constrained with informative priors. This uncertainty scaled up to summary measures of network structure such as connectance and nestedness. Even with informative priors, we are likely to miss many interactions that may occur rarely or under different local conditions.

Overall, we demonstrate the importance of acknowledging the uncertainty inherent in network studies, and the utility of treating interactions as probabilities in pinpointing areas where more study is needed. Most importantly, we stress that networks are best thought of as systems constructed from random variables, the stochastic nature of which must be acknowledged for an accurate representation. Doing so will fundamentally change network analyses and yield greater realism.
Assemblage accumulation curves: A framework for resolving species accumulation in biological communities using DNA sequences
Authors: van der Merwe Marlien , Yap Jia‐Yee S. , Bragg Jason G. , Cristofolini Caroline , Foster Charles S. P. , Ho Simon Y. W. , Rossetto Maurizio
Published: March 2019

The timing and tempo of the processes involved in community assembly are of substantial concern to community ecologists and conservation managers. The fossil record is a valuable source of data for studying past changes in community composition, but it is not always detailed enough to allow the process of community assembly to be resolved at regional or site scales while tracing the trajectories of known species with associated known traits.

We present a three‐step framework for studying present‐day species accumulation through time: DNA sampling from multiple individuals from multiple species within a community; estimates of coalescence times for each species using molecular dating methods; and plotting the accumulation of present‐day species through time using the inferred population ages. Our approach is illustrated using whole‐chloroplast genomes from plants from three rainforest communities in eastern Australia. Expected times to coalescence for multiple species in each community were inferred from pooled high‐throughput sequence libraries. Local assemblage accumulation curves for each community were constructed. We also explored the variation in assemblage accumulation curves of species with different functional traits.

Models of equilibrium species richness informed our null hypothesis and largely explained the shape of the assemblage accumulation curves. They indicated that the complexities of the accumulation process should be explored with additional parameters, for example, allowing species classes with different extinction rates. The assemblage accumulation curves for the study sites showed evidence of recent population expansions within each of the communities. This signal of recent accumulation is consistent with the increase in suitable rainforest habitat that followed the Last Glacial Maximum.

Our method of constructing assemblage accumulation curves provides a simple approach for visualizing species accumulation data. It can be used to test hypotheses such as the relative survival potential of species‐specific ecological attributes. Although our example used single‐nucleotide polymorphisms derived from whole‐chloroplast sequencing, this framework can be applied to mitochondrial genomes and to communities of other organisms.
NAD+ supplementation rejuvenates aged gut adult stem cells
Authors: Igarashi Masaki , Miura Masaomi , Williams Eric , Jaksch Frank , Kadowaki Takashi , Yamauchi Toshimasa , Guarente Leonard
Published: March 2019

The tissue decline due to aging is associated with the deterioration of adult stem cell function. Here we show the number and proliferative activity of intestinal stem cells (ISCs) but not Paneth cells decline during aging, as does ISC function assessed ex vivo. Levels of SIRT1 and activity of mTORC1 also decline with aging. The treatment with the NAD(+) precursor nicotinamide riboside (NR) rejuvenates ISCs from aged mice and reverses an impaired ability to repair gut damage. The effect of NR is blocked by the mTORC1 inhibitor rapamycin or the SIRT1 inhibitor EX527. These findings demonstrate that small molecules affecting the NAD/SIRT1/mTORC1 axis may guide a translational path for maintenance of the intestine during aging.
IL‐1α cleavage by inflammatory caspases of the noncanonical inflammasome controls the senescence‐associated secretory phenotype
Authors: Wiggins Kimberley A. , Parry Aled J. , Cassidy Liam D. , Humphry Melanie , Webster Steve J. , Goodall Jane C. , Narita Masashi , Clarke Murray C. H.
Published: March 2019

Interleukin‐1 alpha (IL‐1α) is a powerful cytokine that modulates immunity, and requires canonical cleavage by calpain for full activity. Mature IL‐1α is produced after inflammasome activation and during cell senescence, but the protease cleaving IL‐1α in these contexts is unknown. We show IL‐1α is activated by caspase‐5 or caspase‐11 cleavage at a conserved site. Caspase‐5 drives cleaved IL‐1α release after human macrophage inflammasome activation, while IL‐1α secretion from murine macrophages only requires caspase‐11, with IL‐1β release needing caspase‐11 and caspase‐1. Importantly, senescent human cells require caspase‐5 for the IL‐1α‐dependent senescence‐associated secretory phenotype (SASP) in vitro, while senescent mouse hepatocytes need caspase‐11 for the SASP‐driven immune surveillance of senescent cells in vivo. Together, we identify IL‐1α as a novel substrate of noncanonical inflammatory caspases and finally provide a mechanism for how IL‐1α is activated during senescence. Thus, targeting caspase‐5 may reduce inflammation and limit the deleterious effects of accumulated senescent cells during disease and Aging.
Long‐term caloric restriction ameliorates deleterious effects of aging on white and brown adipose tissue plasticity
Authors: Corrales Patricia , Vivas Yurena , Izquierdo‐Lahuerta Adriana , Horrillo Daniel , Seoane‐Collazo Patricia , Velasco Ismael , Torres Lucia , Lopez Yamila , Martínez Carmen , López Miguel , Ros Manuel , Obregon Maria Jesus , Medina‐Gomez Gema
Published: March 2019

Age‐related increased adiposity is an important contributory factor in the development of insulin resistance (IR) and is associated with metabolic defects. Caloric restriction (CR) is known to induce weight loss and to decrease adiposity while preventing metabolic risk factors. Here, we show that moderate 20% CR delays early deleterious effects of aging on white and brown adipose tissue (WAT and BAT, respectively) function and improves peripheral IR. To elucidate the role of CR in delaying early signs of aging, young (3 months), middle‐aged (12 months), and old (20 months) mice fed al libitum and middle‐aged and old mice subjected to early‐onset CR were used. We show that impaired plasticity of subcutaneous WAT (scWAT) contributes to IR, which is already evident in middle‐aged mice. Moreover, alteration of thyroid axis status with age is an important factor contributing to BAT dysfunction in middle‐aged animals. Both defects in WAT and BAT/beige cells are ameliorated by CR. Accordingly, CR attenuated the age‐related decline in scWAT function and decreased the extent of fibro‐inflammation. Furthermore, CR promoted scWAT browning. In brief, our study identifies the contribution of scWAT impairment to age‐associated metabolic dysfunction and identifies browning in response to food restriction, as a potential therapeutic strategy to prevent the adverse metabolic effects in middle‐aged animals.
Is Temperature Exogenous? The Impact of Civil Conflict on the Instrumental Climate Record in Sub‐Saharan Africa
Authors: Schultz Kenneth A. , Mankin Justin S.
Published: March 2019

Research into the effects of climate on political and economic outcomes assumes that short‐term variation in weather is exogenous to the phenomena being studied. However, weather data are derived from stations operated by national governments, whose political capacity and stability affect the quality and continuity of coverage. We show that civil conflict risk in sub‐Saharan Africa is negatively correlated with the number and density of weather stations contributing to a country's temperature record. This effect is both cross‐sectional—countries with higher average conflict risk tend to have poorer coverage—and cross‐temporal—civil conflict leads to loss of weather stations. Poor coverage induces a small downward bias in one widely used temperature data set, due to its interpolation method, and increases measurement error, potentially attenuating estimates of the temperature–conflict relationship. Combining multiple observational data sets to reduce measurement error almost doubles the estimated effect of temperature anomalies on civil conflict risk.
Short‐term effect on the ocular circulation induced by unilateral intravitreal injection of aflibercept in age‐related maculopathy
Authors: Mursch‐Edlmayr Anna Sophie , Luft Nikolaus , Podkowinski Dominika , Ring Michael , Schmetterer Leopold , Bolz Matthias
Published: March 2019

Purpose

Intravitreal injection of anti‐vascular endothelial growth factor (anti‐VEGF) is the standard treatment for neovascular age‐related macular degeneration (AMD). As VEGF is a physiological key player for regulating retinal vascular tone, questions have been raised whether the application of anti‐VEGF could induce alterations in ocular perfusion.

Methods

The study included 20 eyes from 20 Caucasian patients with unilateral neovascular AMD and 20 fellow eyes. All eyes were treated with standard intravitreal injection of aflibercept (IVA). Measurements of blood flow at the optic nerve head (ONH) and the choroid were performed with laser speckle flowgraphy (LSFG). The intraocular pressure (IOP), systolic and diastolic blood pressure, heart rate, mean arterial pressure (MAP) and ocular perfusion pressure (OPP) were analysed. Measurements were performed at baseline and repeated immediately after the injection and 30 and 45 min later.

Results

Mean time between injection of aflibercept and first follow‐up was 8:56 ± 4:25 min. The injection led to significant rise in IOP. In the injected eyes, mean blur rate (MBR, i.e. a relative measure of perfusion and the main outcome parameter of LSFG) within the major vessels of the ONH as well as at the entire ONH region decreased significantly (p < 0.001). No change in MBR was observed in the fellow eye. Choroidal blood flow was maintained stable in both eyes.

Conclusion

Intravitreal injection of aflibercept (IVA) led to a short‐term reduction in perfusion only in the treated eye. This was independent from IOP, indicating a direct pharmacological effect. No changes in choroidal perfusion were observed during the first 45 min after the injection.
Anchor me: the benefits and challenges of fiscal responsibility
Authors: Cevik Serhan
Published: March 2019

This paper discusses the benefits and challenges of implementing a rule‐based fiscal responsibility framework, using the Philippines as a case study. It estimates structural measures of the fiscal stance over the period 1980–2016 and applies a stochastic simulation model to determine the optimal set of fiscal rules. The empirical analysis indicates that discretionary fiscal policy has been procyclical, and the degree of procyclicality has increased in recent years. While the national government's nonbinding ceiling on the overall budget deficit is helpful, it does not constitute an appropriate operational target to guide fiscal policy over the economic cycle and necessarily ensure that the fiscal stance meets the government's intertemporal budget constraint. To this end, I use stochastic simulations and show the macroeconomic benefits of a well‐designed fiscal responsibility law that enshrines explicit fiscal rules designed for countercyclical policy and long‐term debt sustainability and an independent fiscal council that improves accountability and transparency.
Editorial: direct‐acting antivirals decrease the frequency of diabetes complications in patients with chronic hepatitis C
Authors: Buchard Benjamin , Cacoub Patrice , Pereira Bruno , Abergel Armand
Published: March 2019

Linked Content

This article is linked to Cacoub et al paper. To view this article, visit
https://doi.org/10.1111/apt.15102.
Editorial: metabolomic biomarkers for colorectal adenocarcinoma and in the differentiation between irritable bowel syndrome and ulcerative colitis in clinical remission – confounded by the gut microbiome? Authors’ reply
Authors: Keshteli Ammar Hassanzadeh , Madsen Karen L. , Mandal Rupasri , Boeckxstaens Guy E. , Bercik Premysl , De Palma Giada , Reed David E. , Wishart David , Vanner Stephen , Dieleman Levinus A.
Published: March 2019

Linked Content

This article is linked to Keshteli et al and Leong et al papers. To view
these articles, visit https://doi.org/10.1111/apt.15141, and https://doi.org/10.1111/apt.15171.
Editorial: biomarker predictors of non‐response to TNFα antagonists — the quest continues. Authors’ reply
Authors: Verstockt Bram , Vermeire Séverine , Ferrante Marc , Breynaert Christine
Published: March 2019

Linked Content

This article is linked to Verstockt et al and Shouval and Ben‐Horin papers. To view these articles, visit https://doi.org/10.1111/apt.15126, and https://doi.org/10.1111/apt.15198.
Letter: the end of duodenal biopsies in coeliac disease? Authors’ reply
Authors: Kurppa Kalle , Fuchs Valma , Kaukinen Katri
Published: March 2019

Linked Content

This article is linked to Fuchs et al and Scicluna and Ellul papers. To
view these articles, visit https://doi.org/10.1111/apt.15109 and https://doi.org/10.1111/apt.15202.
Editorial: diastolic dysfunction seems not to be decisive for survival after transjugular intrahepatic portosystemic stent‐shunt
Authors: Jansen Christian , Trebicka Jonel
Published: March 2019

Linked Content

This article is linked to Armstrong et al paper. To view this article,
visit https://doi.org/10.1111/apt.15164.
Midterm functional outcome after laparoscopic ventral rectopexy for external rectal prolapse
Authors: Tsunoda Akira , Takahashi Tomoko , Matsuda Satoshi , Oka Naoki , Kusanagi Hiroshi
Published: March 2019

Introduction

Although long‐term crude outcomes of laparoscopic ventral rectopexy for external rectal prolapse (ERP) have been documented, repetitive functional and quality of life (QOL) assessments are scarce. This study assessed midterm annual functional results and QOL after laparoscopic ventral rectopexy for ERP.

Methods

This study consisted of 58 patients and was a retrospective analysis of prospectively collected data. The Fecal Incontinence Severity Index, the Constipation Scoring System, and QOL instruments (ie 36‐item Short‐Form Health Survey and Fecal Incontinence Quality of Life scale) were administered before and after operation.

Results

There was no mortality or major morbidity. After a median follow‐up of 49 months (6‐92 months), recurrence of ERP was noted in one patient (2%). There were no mesh‐related complications. The median Fecal Incontinence Severity Index score was significantly reduced at 3 months (34 [10‐61] vs 12 [0‐50], P < 0.0001) and remained significantly reduced for 5 years. The median Constipation Scoring System score was significantly reduced at 3 months (14 [9‐20] vs 7 [0‐16], P < 0.0001) and remained significantly reduced for 4 years. No patients developed new‐onset constipation. All of the Fecal Incontinence Quality of Life scales significantly improved overtime for 4 years. All of the 36‐item Short‐Form Health Survey scales were significantly improved at 3 and 6 months, but none of the scales significantly improved after 2 years.

Conclusion

Laparoscopic ventral rectopexy for ERP was associated with low morbidity, low recurrence, and a midterm improvement in function and fecal incontinence‐specific QOL.
Reptarenaviruses in apparently healthy snakes in an Australian zoological collection
Authors: Hyndman TH , Marschang RE , Bruce M , Clark P , Vitali SD
Published: March 2019

Background

Inclusion body disease (IBD) is a disease of snakes with a global distribution and has recently been shown to be caused by reptarenaviruses. Testing for this group of viruses in asymptomatic snakes allows the association between infection and disease to be further elucidated.

Methods

A reptarenavirus was detected by RT‐PCR in a reticulated python (Malayopython reticulatus) from an Australian zoological collection that was open‐mouth breathing and had erythematous oral mucosa. Another 27 pythons, 4 elapids, 2 colubrids and 2 boas from this collection were then screened. From these animals, swabs, whole blood and/or tissue were tested for reptarenaviruses by RT‐PCR. Additionally, blood films from 10 snakes were examined by light microscopy for the presence of inclusion bodies. The majority of samples were collected over a 484‐day period.

Results

A total of 8 animals were RT‐PCR‐positive (8/36 = 22.2%): 6 were pythons, 1 was a corn snake (Pantherophis guttatus) and 1 was a Madagascar tree boa (Sanzinia madagascariensis). From them, 57 samples were collected, but only one from each animal was RT‐PCR‐positive (8/57 = 14.0%). From all 36 animals in this study, 8/182 samples were RT‐PCR‐positive (4.4%). Inclusion bodies were not recognised in any of the blood films. Only the reticulated python showed signs of illness, which improved without any further intervention. All other RT‐PCR‐positive snakes were apparently healthy throughout the duration of the study.

Conclusion

This study showed a weak association between the presence of reptarenaviruses and disease. Testing serially collected swab and whole‐blood samples increased the number of animals in which reptarenaviruses were detected.
Maximising business returns to corporate social responsibility communication: An empirical test
Authors: Pérez Andrea , del Mar García de los Salmones María , Liu Matthew Tingchi
Published: March 2019

Based on a classic conceptual model of corporate social responsibility (CSR) communication, we developed an empirical research study to test how several aspects of CSR message content (i.e., issue importance, impact, motives, fit, commitment) are associated with external support responses (i.e., purchase, advocacy). We also tested the moderating role of stakeholder‐ and company‐specific factors (i.e., issue support and industry, respectively) in the proposed model. Data were collected from 302 participants who evaluated the same CSR information displayed in the websites of a fictitious bank and a fictitious restaurant chain. The findings suggest that better perceptions on how the CSR message reinforces issue importance, corporate CSR impact and altruistic motives lead to higher purchase and advocacy intentions. CSR fit is related only to advocacy, while CSR commitment does not have any significant impact on participants’ responses. Some new interdependence relationships are also identified among issue importance, motives, fit, and commitment. The moderating role of issue support and industry is confirmed.
The craftivists: Pushing for affective, materially informed pedagogy
Authors: Rowsell Jennifer , Shillitoe Mark
Published: March 2019

The idea of making as a form of activism or, as we refer to it in this paper, craftivism, underpins our ambition to transform pedagogical environments into spaces of possibility through sensory and affective making practices. A craftivist agenda pushes for open teaching and learning with materials so that students can inhabit a what if space which ruptures institutional time and space. Beginning with a theorization of disruptive making and dissensus and then moving on to foreground a materialist stance on making, the paper illustrates how students experience materialities across two very different classroom environments and how these experiences led to greater presence, voice and agency for students. There is an underlying focus in the paper on embodied responses and affective flows. After theorizing craftivism, there are three sections that explore making, teaching and feeling through craftivist, postdigital methods.
A phase III randomized, multicentre, double blind, active controlled trial to compare the efficacy and safety of two different anagrelide formulations in patients with essential thrombocythaemia – the TEAM‐ET 2·0 trial
Authors: Gisslinger Heinz , Buxhofer‐Ausch Veronika , Hodisch Juri , Radinoff Atanas , Karyagina Elena , Kyrcz‐Krzemień Slawomira , Abdulkadyrov Kudrat , Gerbutavicius Rolandas , Melikyan Anait , Burgstaller Sonja , Hus Marek , Kłoczko Janusz , Yablokova Vera , Tzvetkov Nikolay , Całbecka Malgorzata , Shneyder Tatyana , Warzocha Krzysztof , Jurgutis Mindaugas , Kaplanov Kamil , Jilma Bernd , Schoergenhofer Christian , Klade Christoph
Published: March 2019

Anagrelide is an established treatment option for essential thrombocythaemia (ET). A prolonged release formulation was developed with the aim of reducing dosing frequency and improving tolerability, without diminishing efficacy. This multicentre, randomized, double blind, active‐controlled, non‐inferiority trial investigated the efficacy, safety and tolerability of anagrelide prolonged release (A‐PR) over a reference product in high‐risk ET patients, either anagrelide‐naïve or ‐experienced. In a 6 to 12‐week titration period the individual dose for the consecutive 4‐week maintenance period was identified. The primary endpoint was the mean platelet count during the maintenance period (3 consecutive measurements, day 0, 14, 28). Of 112 included patients 106 were randomized. The mean screening platelet counts were 822 × 109/l (95% confidence interval (CI) 707–936 × 109/l) and 797 × 109/l (95% CI 708–883 × 109/l) for A‐PR and the reference product, respectively. Both treatments effectively reduced platelet counts, to mean 281 × 109/l for A‐PR (95% CI 254–311) and 305 × 109/l (95% CI 276–337) for the reference product (P < 0·0001, for non‐inferiority). Safety and tolerability were comparable between both drugs. The novel prolonged‐release formulation was equally effective and well tolerated compared to the reference product. A‐PR provides a more convenient dosing schedule and will offer an alternative to licensed immediate‐release anagrelide formulations.
Comparison of Rituximab originator (MabThera) to biosimilar (Truxima) in patients with immune‐mediated thrombotic thrombocytopenic purpura
Authors: Stubbs Matthew J. , Low Ryan , McGuckin Siobhan , Newton Rosalind , Thomas Mari , Westwood John P. , Shah Raakhee , Cheesman Simon , Scully Marie A.
Published: March 2019

Immune thrombotic thrombocytopenic purpura (iTTP) is an acute, multisystem thrombotic microangiopathy mediated by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) autoantibodies. Immunosuppression with anti‐CD20 therapy is the mainstay of treatment. MabThera's patent has now expired and biosimilars have been approved. Eighty‐four consecutive patient episodes over 2 years, prior to and following our switch to Truxima are presented. Day 1 (D1), Day 28 (D28) and 3‐month platelet counts, ADAMTS13 activity, and CD19 levels, adverse reactions and infective complications were recorded. Platelet counts were not significantly different between acute MabThera and Truxima treatment (D1 P = 0.085, D28 P = 0.77, 3 months P = 0.71) and electively (D1 P = 0.79, D28 P = 0.68, 3 months P = 0.99). ADAMTS13 recovery also was not significantly different acutely (D1 P = 0.99, D28 P = 0.27, 3 months P = 0.26) and electively (D1 P = 0.59, D28 P = 0.61, 3 months P = 0.34). CD19% depletion at D1 and 3 months was not significantly different acutely (D1 P = 0.52, 3 months P = 0.56) and electively (D1 P = 0.22, 3 months P = 0.19). Infusion reactions and infective complications were comparable with both therapies. This is the first series of the Rituximab biosimilar Truxima to be reported in iTTP, demonstrating equivalence to MabThera in terms of ADAMTS13 recovery, CD19 depletion, and platelet count at D28 and 3 months post‐administration, with comparable infusion and infective complications. The financial benefit of the biosimilar anti‐CD20 is considerable.
EFFECT OF OIL PRICES ON STOCK MARKETS: EVIDENCE FROM NEW GENERATION OF STAR MODEL
Authors: Harb Nermeen , Abdelsalam Mamdouh Abdelmoula M.
Published: March 2019

This paper aims to introduce an evidence of new generations of smooth transition regression model (STAR). It proposes two different forms of STAR model. First: a time varying STAR model (TVSTAR), which identify the estimated coefficients at each point of time. Second: a full specification STAR model (FSSTAR) which provides a consistent estimate even in the existence of some measurement errors, omitted variables and even if the true functional form is unknown. This study will consider the two proposed models and the traditional STAR model to examine the nonlinear relation between oil price and stock market index for two countries (Egypt and Turkey). Our results confirm the existing of a non‐linear relation between oil prices and stock return for both countries. The suggested models gives more accurate information about the time varying effect of oil price changes on stock markets and robust forecasts.
Determining kinematic order and relative age of faulting via flexural‐kinematic restoration: A case study in far western Nepal
Authors: Olsen Joshua E. S. , McQuarrie Nadine , Robinson Delores M.
Published: March 2019

Forward modeled, balanced cross sections that account for the flexural response to thrust loading and erosional unloading can verify and refine the kinematic sequence of deformation in fold‐thrust belts as well as help assess the validity of a balanced cross section. Results from flexural‐kinematic reconstructions that indicate either the cross section, the kinematic order or both are invalid include: (a) a predicted final topography that is dramatically different from the actual topography; (b) large normal fault or thrust fault bounded synorogenic basins that are not present in the mapped geology; and/or (c) an exhumation history that is not consistent with provenance records in the basin or measured thermochronometers. Where detailed measured foreland basin sections exist, flexural‐kinematic modeling of fold‐thrust belt deformation, including out‐of‐sequence (OOS) faults can predict a foreland basin evolution that can be compared to measured data. The modeling process creates a “pseudostratigraphy” in the modeled foreland. The pseudostratigraphy and predicted provenance of each modeled stratigraphic increment can be directly compared to measured stratigraphic sections. We present a case study using two cross sections through the Himalaya of far western Nepal (Api and Simikot) to assess the validity of the section geometries and the resulting kinematic histories, displacement rates, flexural wave response and predicted provenance for both sections. Insights from combining the flexural‐kinematic models with existing stratigraphic data include: (a) Changing the order of proposed OOS and normal faults to earlier in the evolution of the fold‐thrust belt was necessary to reproduce the foreland provenance data. We argue that OOS thrust and normal faults in the Api section occurred between 11 and 4 Ma. (b) Published shortening estimates for the Simikot cross section are too high (>50 km), resulting in unrealistic shortening rates up to 80 mm/yr between 25 and 20 Ma. (c) Flexural forward models with and without an additional sediment loading modeling step indicate that while sediment loading does not have a measurable effect on the magnitude and location of erosion within the fold‐thrust belt, it does have a small effect on accumulation rates and thus the predicted age of stratigraphic boundaries when compared to measured stratigraphic thicknesses and age. Thickness difference range from 0.2 to 0.5 km and can result in predicted age differences of ca. 1 Ma. Accounting for both flexural isostacy and erosion can eliminate unviable kinematic sequences and when combined with provenance data from measured stratigraphic sections, can provide insight into the order, age and rate of deformation.
Synthesis and antitumor activity of isolongifoleno[7,8‐d]thiazolo[3,2‐a]pyrimidine derivatives via enhancing ROS level
Authors: Ma Chonghui , Wang Yunyun , Dong Fuhao , Wang Zhonglong , Zhao Yuxun , Shan Yu , Gu Wen , Wang Shifa
Published: March 2019

A series of novel isolongifoleno[7,8‐d]thiazolo[3,2‐a]pyrimidine derivatives (4a–4x) were synthesized from isolongifolanone according fragment‐based design strategy, and their anticancer activity against human aortic smooth muscle cells (HASMC), human breast cancer (MCF‐7) cells, human cervical cancer (HeLa) cells, and human liver cancer (HepG2) cells were investigated. Results of the anticancer activity illustrated that most of the compounds showed potent antitumor activity and compound 4i proved to be the most active derivative with IC50 values of 0.33 ± 0.24 (for MCF‐7 cells), 0.52 ± 0.13 (for HeLa cells), and 3.09 ± 0.11 μM (for HepG2 cells), respectively. Moreover, we assessed the effects of 4i on cell apoptosis, cell cycle distribution, mitochondrial membrane potential, and reactive oxygen species (ROS) generation. The results indicated that compound 4i altered mitochondrial membrane potential and produced ROS leading to cell apoptosis of MCF‐7 cells in a dose‐dependent manner, however, without affecting cell cycle progression. These findings suggested that 4i was an effective compound and provided a promising candidate for anticancer drugs.
Peri‐implant marginal bone loss rate pre‐ and post‐loading: An exploratory analysis of associated factors
Authors: Acharya Aneesha , Leung Ming Chi Terrence , Ng King Tung , Fan Michael H.M. , Fokas George , Mattheos Nikos
Published: March 2019

Objectives

To perform an exploratory analysis of factors influencing annual rates of peri‐implant marginal bone loss (RBL) calculated over different time frames, at implants unaffected by peri‐implantitis.

Material and methods

A total of 154 implants from 86 patients were reviewed at 1.6–6.8 years after placement. Marginal bone levels (MBL) were assessed on intraoral radiographs at three time‐points: immediately post‐placement, time of loading, and least 1‐year post‐loading. RBLs (mm/year) were computed using these three time frames and corresponding MBL changes as: RBL placement‐loading, RBL loading‐review, RBL placement‐review. Exploratory ordination of three RBLs, corresponding time durations, and 17 background factors were used for visualization. Hierarchical linear mixed‐effects models (MEM) with predictor selection were applied to RBL outcomes. The correlation of actual MBL with MBLs predicted by RBL placement‐loading and RBL loading‐review was tested.

Results

Median RBL placement‐loading was 0.9 mm/year (IQR = 2.02), loading‐review was 0.06 mm/year (IQR = 0.16), and overall RBL placement‐review was 0.21 mm/year (IQR = 0.33). Among‐patient variance was highest for RBL placement‐loading (SD = 0.66). Longer time predicted lower RBL in all time frames. Shorter time of loading significantly predicted lower RBL placement‐review. Augmentation predicted lower RBL placement‐loading, while anterior location and older age predicted lower RBLs placement‐loading placement‐review. Only MBL projected using RBL placement‐loading significantly correlated with actual MBL.

Conclusions

Exploratory analysis indicated RBL varied with the time duration used for calculation in pre‐ and post‐loading, and overall periods. In each period, RBL declined with increasing time. Earlier loading predicted lower overall RBL. Higher pre‐loading RBL predicted worse actual bone level.
Lifetime change in central and peripheral haemodynamics in relation to exercise capacity
Authors: Lind Lars , Lampa Erik
Published: March 2019

Exercise capacity as well as many resting central and peripheral haemodynamic features declines by age. We aimed to investigate which haemodynamic features change the most during life and which change in parallel to exercise capacity. We performed a maximal bicycle exercise test with gas exchange in 103 healthy subjects (24 young, 55 middle‐aged and 24 elderly). Endothelial function, arterial compliance/stiffness and heart rate variability (HRV) were evaluated, and the myocardium and carotid arteries were investigated by ultrasound. Exercise capacity declined by almost 50% over the lifespan. Several markers reflecting arterial compliance/stiffness and HRV, as well as carotid intima–media thickness (IMT), showed lifetime impairments by >100%, while markers of LV systolic function, diastolic blood pressure and carotid artery blood flow showed only minor changes with age. The decline in exercise capacity clusters closely with many other variables measured during the exercise test, but also to resting vital capacity, left ventricular end‐diastolic diameter and resting gas exchange (VO2, VCO2) to a lesser degree. Resting vital capacity was closely related to exercise capacity in the middle‐aged group. We conclude that many of the resting markers of central and peripheral haemodynamics declined during life, in parallel to the decline in exercise capacity. However, some haemodynamic features, such as LF/HF ratio at HRV, stiffness index beta of the carotid artery, and heart rate reserve at the exercise test, showed a more exaggerated decline, indicating that those are not closely linked to exercise capacity.
Exposure–Response Modeling and Simulation of Progression‐Free Survival and Adverse Events of Sorafenib Treatment in Patients With Advanced Thyroid Cancer
Authors: Grevel Joachim , Jentsch Garrit , Austin Rupert , Prins Nicolaas H. , Lettieri John , Mitchell David , Huang Funan , Brose Marcia S. , Schlumberger Martin , Meinhardt Gerold , Peña Carol E. A. , Ploeger Bart A.
Published: March 2019

Sorafenib is an oral multikinase inhibitor approved for the treatment of differentiated thyroid carcinoma (DTC), renal cell carcinoma, and hepatocellular carcinoma. In the phase III DECISION trial in patients with DTC, sorafenib exposure and the incidence of some adverse events (AEs) were higher than in previous trials; therefore, we analyzed exposure–response relationships, including progression‐free survival (PFS) and selected AEs in patients with DTC. A novel, stratified prediction‐corrected visual predictive check (pc‐VPC) was developed to show robustness of the exposure–response relationships. Time‐to‐event simulations confirmed the benefit of the recommended dosing schedule of 800 mg/day: initial doses of 800 mg/day were associated with the highest PFS, whereas lower doses (600 or 400 mg/day) were associated with improved tolerability but reduced PFS. A simulated dose‐reduction strategy of 800 mg/day for an initial two cycles followed by dose reductions seemed likely to maintain efficacy while possibly mitigating selected AEs (e.g., diarrhea and hand‐foot skin reactions).
Multiple subcutaneous swellings in a young woman
Authors: Kapatia Gargi , Gupta Parikshaa , Jain Khimit , Keshavamurthy Vinay , Rajwanshi Arvind
Published: March 2019

Pilomatricoma is a relatively rare, benign skin appendageal neoplasm with predilection for head and neck region, young age, and female sex. Cytological diagnosis is often challenging owing to the lack of awareness and failure to identify the characteristic cytomorphological features, often leading to misdiagnoses. Development of multiple pilomatricomas is very rare, with only a few cases reported in the literature. We report a case of a young woman presenting with multiple pilomatricomas, which could be accurately diagnosed on fine needle aspiration cytology.
Systemische Therapien bei Pityriasis rubra pilaris: eine systematische Übersicht
Authors: Kromer Christian , Sabat Robert , Celis Daniel , Mössner Rotraut
Published: March 2019

Pityriasis rubra pilaris (PRP) ist eine seltene papulosquamöse Erkrankung. Die Behandlung ist schwierig; das therapeutische Arsenal umfasst topische Corticosteroide, Phototherapie, klassische Systemtherapien wie Retinoide oder Immunsuppressiva sowie, seit Kurzem, Biologika. Die relative Wirksamkeit der Behandlungen ist jedoch unklar. Unser Ziel war die Durchsicht der Literatur zur systemischen Behandlung der PRP. In PubMed und der Cochrane Library wurde eine systematische Recherche bis zum 5. September 2017 durchgeführt. Eingeschlossen wurden Studien, in denen systemische Behandlungen der PRP (ausgenommen historische Behandlungen) geprüft wurden. Insgesamt erfüllten 182 Studien die vorgegebenen Einschlusskriterien; sie enthielten Daten über 475 Patienten und 652 Behandlungszyklen. 42,0 % (225/514) aller mit Retinoiden behandelten Patienten sprachen hervorragend an (Isotretinoin: 61,1 % [102/167], Etretinat: 47 % [54/115] und Acitretin: 24,7 % [43/174]), verglichen mit einer hervorragenden Ansprechrate von 33,1 % (53/160) unter Methotrexat. Therapien mit Biologika waren bei 51,0 % der Patienten (71/133) erfolgreich (Ustekinumab: 62,5 % [10/16], Infliximab: 57,1 % [28/49], Etanercept: 53,3 % [16/30] und Adalimumab: 46,4 % [13/28]). In dieser Übersicht werden Wirksamkeit, Nebenwirkungen, Erfahrungen und Arzneimittelkosten gegeneinander abgewogen und es wird ein Behandlungsregime mit Isotretinoin als Erstlinien‐, Methotrexat als Zweitlinien‐ und Biologika als Drittlinienbehandlung vorgeschlagen.
S2k guidelines for skin and soft tissue infections Excerpts from the S2k guidelines for “calculated initial parenteral treatment of bacterial infections in adults – update 2018“
Authors: Sunderkötter Cord , Becker Karsten , Eckmann Christian , Graninger Wolfgang , Kujath Peter , Schöfer Helmut
Published: March 2019

These first German S2k guidelines for bacterial skin and soft tissue infections were developed as one chapter of the recommendations for “calculated initial parenteral treatment of bacterial infections” issued under the auspices of the Paul‐Ehrlich Society, of which the main part is presented here.

Well‐calculated antibiotic therapies require precise diagnostic criteria. Erysipelas is defined as non‐purulent infection considered to be caused by beta‐hemolytic strepto­cocci. It is diagnosed clinically by its bright‐red erythema and early fever or chills at disease onset. Penicillin is the treatment of choice. Limited soft tissue infection (cellulitis) is usually caused by Staphylococcus (S.) aureus, frequently originates from chronic wounds and presents with a more violaceous‐red hue and only rarely with initial fever or chills. Treatment consists of first‐ or second‐­generation cephalosporins or flucloxacillin (IV).

Severe cellulitis is a purulent, partially necrotic infection which extends through tissue boundaries to fascias and requires surgical management in addition to antibiotics. Moreover, it frequently fulfills the criteria for “complicated soft tissue infections”, as previously defined by the Food and Drug Administration for use in clinical trials (they include comorbidities such as uncontrolled diabetes, peripheral artery disease, neutropenia). It requires antibiotics which besides S. aureus target anaerobic and/or gramnegative bacteria. The rare so‐called necrotizing skin and soft tissue infections represent a distinct entity. They are characterized by rapid, life‐threatening progression due to special bacterial toxins that cause ischemic necrosis and shock and need rapid and thorough debridement in addition to appropriate antibiotics. For cutaneous abscesses the first‐line treatment is adequate drainage. Additional antibiotic therapy is required only under certain circumstances (e.g., involvement of the face, hands, or anogenital region, or if drainage is somehow complicated).

The present guidelines also contain consensus‐based recommendations for higher doses of antibiotics than those approved or usually given in clinical trials. The goal is to deliver rational antibiotic treatment that is both effective and well‐tolerated and that exerts no unnecessary selection pressure in terms of multidrug resistance.
Bakterielle sexuell übertragbare Infektionen
Authors: Buder Susanne , Schöfer Helmut , Meyer Thomas , Bremer Viviane , Kohl Peter K. , Skaletz‐Rorowski Adriane , Brockmeyer Norbert
Published: March 2019

Bakterielle sexuell übertragbare Infektionen (STI) zeigen seit Jahren weltweit eine deutliche Zunahme. In Deutschland wird diese Tatsache durch steigende Meldezahlen für Syphilis bestätigt. Auch für die nicht meldepflichtigen STI Gonorrhoe, Chlamydia‐trachomatis‐ und Mycoplasma‐genitalium‐Infektionen wird eine zunehmende Inzidenz beobachtet. Entscheidend für die Weiterverbreitung ist, dass das breite klinische Spektrum, welches neben Urogenitalsitus auch Pharynx und Rektum einbezieht, durch eine hohe Zahl asymptomatischer Verläufe ergänzt wird. Neue Real‐Time‐Multiplex‐Diagnostikverfahren ermöglichen einen schnellen und gezielten Nachweis von STI‐Erregern. Die häufigste bakterielle STI ist die urogenitale Chlamydieninfektion mit den Serovaren D–K, die besonders bei jungen Erwachsenen auftritt. Einer Chlamydien‐Proktitis kann eine Infektion mit L‐Serovaren und damit eine Lymphogranuloma‐venereum (LGV)‐Infektion zugrunde liegen. Neisseria (N.) gonorrhoeae zeigte in den letzten Jahren eine starke Resistenzentwicklung mit Ausbildung von Einzel‐ und Multiresistenzen gegenüber bisher gängigen Antibiotika. Daher ist für N. gonorrhoeae zusätzlich zum nucleic acid amplification test (NAAT) eine kulturelle Empfindlichkeitstestung durchzuführen. Auch für Mycoplasma genitalium sind Resistenzentwicklungen bekannt, die eine Therapie erschweren können.
Difficulty in the diagnosis of isolated immunoglobulin G4‐related sclerosing cholangitis
Authors: Nakazawa Takahiro
Published: March 2019

This Editorial refers to the article by Y. Takagi et al., p 422–430 of this issue.
Proprotein convertase subtilisin/kexin type 9 and mortality in patients starting hemodialysis
Authors: Strålberg Towe , Nordenskjöld Anna , Cao Yang , Kublickiene Karolina , Nilsson Erik
Published: March 2019

Background

Cardiovascular events are the leading cause of death in end stage renal disease (ESRD), but traditional markers of dyslipidemia are not clearly associated with cardiovascular risk in this population. Proprotein Convertase Subtilsin/Kexin type 9 (PCSK‐9) could be of interest as a novel cardiovascular risk marker in ESRD due to the emergence of lipid lowering therapy based on PCSK‐9 inhibition. The aim of the present study was to investigate if the convertase PCSK‐9 is a potential risk marker for mortality among patients starting haemodialysis treatment.

Materials and methods

This is a cohort study of 265 patients starting haemodialysis between 1991‐2009, with 3 years follow‐up. The association between baseline PCSK‐9 levels and mortality was assessed using Cox proportional hazards‐ and quantile regression models, with adjustment for potential confounders.

Results

PCSK‐9 levels at initiation of haemodialysis were associated to mortality in multivariable adjusted analysis. PCSK‐9 levels exhibited an U‐shaped association to mortality. Inclusion of the quadratic term of PCSK‐9 in regression modelling optimized model performance. At baseline, PCSK‐9 levels had positive correlations to Davies comorbidity score, haemoglobin and C‐reactive protein while negative correlations were found for high‐density lipoprotein and total cholesterol. PCSK‐9 levels were higher in statin users and patients with a history of cardiovascular disease.

Conclusions

This study shows, for the first time, that the level of PCSK‐9 is associated with all‐cause mortality in haemodialysis patients, independently of a number of potential confounders.
Species‐rich boreal forests grew more and suffered less mortality than species‐poor forests under the environmental change of the past half‐century
Authors: Hisano Masumi , Chen Han Y. H. , Searle Eric B. , Reich Peter B.
Published: March 2019

Climate and other global environmental changes are major threats to ecosystem functioning and biodiversity. However, the importance of plant diversity in mitigating the responses of functioning of natural ecosystems to long‐term environmental change remains unclear. Using inventory data of boreal forests of western Canada from 1958 to 2011, we found that aboveground biomass growth increased over time in species‐rich forests but decreased in species‐poor forests, and importantly, aboveground biomass loss from tree mortality was smaller in species‐rich than species‐poor forests. A further analysis indicated that growth of species‐rich (but not species‐poor) forests was statistically positively associated with rising CO2, and that mortality in species‐poor forests increased more as climate moisture availability decreased than it did in species‐rich forests. In contrast, growth decreased and mortality increased as the climate warmed regardless of species diversity. Our results suggest that promoting high tree diversity may help reduce the climate and environmental change vulnerability of boreal forests.