bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of steroid use as a key performance indicator in inflammatory bowel disease—analysis of data from 2385 UK patients
Authors: Selinger Christian P. , Parkes Gareth C. , Bassi Ash , Limdi Jimmy K. , Ludlow Helen , Patel Pritash , Smith Melissa , Saluke Santosh , Ndlovu Zandile , George Becky , Saunders John , Adamson Mark , Fraser Aileen , Robinson Jenna , Donovan Fiona , Parisi Ioanna , Tidbury Jude , Gray Lynn , Pollok Richard , Scott Glyn , Raine Tim
Published: October 2019

Background

Patients with IBD are at risk of excess corticosteroids.

Aims

To assess steroid excess in a large IBD cohort and test associations with quality improvement and prescribing.

Methods

Steroid exposure was recorded for outpatients attending 19 centres and associated factors analysed. Measures taken to avoid excess were assessed.

Results

Of 2385 patients, 28% received steroids in the preceding 12 months. 14.8% had steroid excess or dependency. Steroid use was significantly lower at ‘intervention centres’ which participated in a quality improvement programme (exposure: 23.8% vs 31.0%, P < .001; excess 11.5% vs 17.1%, P < .001). At intervention centres, steroid use fell from 2015 to 2017 (steroid exposure 30.0%‐23.8%, P = .003; steroid excess 13.8%‐11.5%, P = .17). Steroid excess was judged avoidable in 50.7%. Factors independently associated with reduced steroid excess in Crohn's disease included maintenance with anti‐TNF agents (OR 0.61 [95% CI 0.24‐0.95]), treatment in a centre with a multi‐disciplinary team (OR 0.54 [95% CI 0.20‐0.86]) and treatment at an intervention centre (OR 0.72 [95% CI 0.46‐0.97]). Treatment with 5‐ASA in CD was associated with higher rates of steroid excess (OR 1.72 [95% CI 1.24‐2.09]). In ulcerative colitis (UC), thiopurine monotherapy was associated with steroid excess (OR 1.97 [95% CI 1.19‐3.01]) and treatment at an intervention centre with less steroid excess (OR 0.72 [95% CI 0.45‐0.95]).

Conclusions

This study validates steroid assessment as a meaningful quality measure and provides a benchmark for this performance indicator in a large cohort. A programme of quality improvement was associated with lower steroid use.
Southeast Asia's transboundary haze pollution: Unravelling the inconvenient truth
Authors: Zhang J.J. , Savage Victor R.
Published: October 2019

This paper examines the political intricacies inherent in the management of Southeast Asia's transboundary haze pollution. It argues for a scalar perspective in understanding the complexities of the haze problem. The so‐called ‘inconvenient truth’ is unravelled by teasing out some issues in the national and regional political ecologies, and the challenges of synchronising co‐operation at the national, regional and global scales. Discussion shows that the ‘environment’ takes on different meanings at each scale, and both Indonesia and the Association of Southeast Asian Nations (ASEAN) need to recognise this in order to engage more effectively with the transboundary environmental issue. Specifically, inadequate management of forest resources in Indonesia, ASEAN's principle of ‘non‐interference’ and a lack of a holistic ecosystem perspective are amongst some of the interconnected issues addressed. The paper calls for a greater awareness of structural weaknesses in the management of forest resources and a change in ASEAN's environmental paradigm to a more holistic ecosystem perspective that prioritises not just environmental and human health, but also a healthy and sustainable ecosystem.
Pomalidomide plus low‐dose dexamethasone in relapsed refractory multiple myeloma after lenalidomide treatment failure
Authors: Siegel David S. , Schiller Gary J. , Song Kevin W. , Agajanian Richy , Stockerl‐Goldstein Keith , Kaya Hakan , Sebag Michael , Samaras Christy , Malek Ehsan , Talamo Giampaolo , Seet Christopher S. , Mouro Jorge , Pierceall William E. , Zafar Faiza , Chung Weiyuan , Srinivasan Shankar , Agarwal Amit , Bahlis Nizar J.
Published: October 2019

Patients with relapsed/refractory multiple myeloma (RRMM) for whom the benefits of lenalidomide have been exhausted in early treatment lines need effective therapies. In cohort A of the phase 2 MM‐014 trial, we examined the safety and efficacy of pomalidomide plus low‐dose dexamethasone immediately after lenalidomide‐based treatment failure in patients with RRMM and two prior lines of therapy. Pomalidomide 4 mg was given on days 1 to 21 of 28‐day cycles. Dexamethasone 40 mg (20 mg for patients aged >75 years) was given on days 1, 8, 15 and 22 of 28‐day cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression‐free survival (PFS), overall survival (OS) and safety. The intention‐to‐treat population comprised 56 patients; all received prior lenalidomide (87·5% lenalidomide refractory) and 39 (69·6%) received prior bortezomib. ORR was 32·1% (28·2% in the prior‐bortezomib subgroup). Median PFS was 12·2 months (7·9 months in the prior‐bortezomib subgroup). Median OS was 41·7 months (38·6 months in the prior‐bortezomib subgroup). The most common grade 3/4 treatment‐emergent adverse events were anaemia (25·0%), pneumonia (14·3%) and fatigue (14·3%). These findings support earlier sequencing of pomalidomide‐based therapy in lenalidomide‐pretreated patients with RRMM, including those who have become refractory to lenalidomide.

Trial registration: www.ClinicalTrials.gov identifier NCT01946477.
Opioids differentially modulate two synapses important for pain processing in the amygdala
Authors: Kissiwaa Sarah A. , Patel Sahil D. , Winters Bryony L. , Bagley Elena E.
Published: October 2019

Background and Purpose

Pain is a subjective experience involving sensory discriminative and emotionally aversive components. Consistent with its role in pain processing and emotions, the amygdala modulates the aversive component of pain. The laterocapsular region of the central nucleus of the amygdala (CeLC) receives nociceptive information from the parabrachial nucleus (PB) and polymodal, including nociceptive, inputs from the basolateral nucleus of the amygdala (BLA). Opioids are strong analgesics and reduce both the sensory discriminative and the affective component of pain. However, it is unknown whether opioids regulate activity at the two nociceptive inputs to the amygdala.

Experimental Approach

Using whole‐cell electrophysiology, optogenetics, and immunohistochemistry, we investigated whether opioids inhibit the rat PB–CeLC and BLA–CeLC synapses.

Key Results

Opioids inhibited glutamate release at the PB–CeLC and BLA–CeLC synapses. Opioid inhibition is via the μ‐receptor at the PB–CeLC synapse, while at the BLA–CeLC synapse, inhibition is via μ‐receptors in all neurons and via δ‐receptors and κ‐receptors in a subset of neurons.

Conclusions and Implications

Agonists of μ‐receptors inhibited two of the synaptic inputs carrying nociceptive information into the laterocapsular amygdala. Therefore, μ‐receptor agonists, such as morphine, will inhibit glutamate release from PB and BLA in the CeLC, and this could serve as a mechanism through which opioids reduce the affective component of pain and pain‐induced associative learning. The lower than expected regulation of BLA synaptic outputs by δ‐receptors does not support the proposal that opioid receptor subtypes segregate into subnuclei of brain regions.
Reduction in HPV16/18 prevalence among young women with high‐grade cervical lesions following the Japanese HPV vaccination program
Authors: Matsumoto Koji , Yaegashi Nobuo , Iwata Takashi , Yamamoto Kasumi , Aoki Yoichi , Okadome Masao , Ushijima Kimio , Kamiura Shoji , Takehara Kazuhiro , Horie Koji , Tasaka Nobutaka , Sonoda Kenzo , Takei Yuji , Aoki Yoichi , Konnai Katsuyuki , Katabuchi Hidetaka , Nakamura Keiichiro , Ishikawa Mitsuya , Watari Hidemichi , Yoshida Hiroyuki , Matsumura Noriomi , Nakai Hidekatsu , Shigeta Shogo , Takahashi Fumiaki , Noda Kiichiro , Yoshikawa Hiroyuki ,   for the MINT Study Group
Published: October 2019

The Japanese government began a human papillomavirus (HPV) vaccination program for girls aged 12‐16 years in 2010 but withdrew its recommendation in 2013 because of potential adverse effects, leading to drastically reduced vaccination uptake. To evaluate population‐level effects of HPV vaccination, women younger than 40 years of age newly diagnosed with cervical intraepithelial neoplasia grade 1‐3 (CIN1‐3), adenocarcinoma in situ (AIS), or invasive cervical cancer (ICC) have been registered at 21 participating institutes each year since 2012. A total of 7709 women were registered during 2012‐2017, of which 5045 were HPV genotyped. Declining trends in prevalence of vaccine types HPV16 and HPV18 during a 6‐year period were observed in CIN1 (50.0% to 0.0%, Ptrend < .0001) and CIN2‐3/AIS (83.3% to 45.0%, Ptrend = .07) only among women younger than 25 years of age. Overall, HPV vaccination reduced the proportion of HPV16/18‐attributable CIN2‐3/AIS from 47.7% to 33.0% (P = .003): from 43.5% to 12.5% as routine vaccination (P = .08) and from 47.8% to 36.7% as catch‐up vaccination (P = .04). The HPV16/18 prevalence in CIN2‐3/AIS cases was significantly reduced among female individuals who received their first vaccination at age 20 years or younger (P = .02). We could not evaluate vaccination effects on ICC owing to low incidence of ICC among women aged less than 25 years. We found HPV vaccination to be effective in protecting against HPV16/18‐positive CIN/AIS in Japan; however, our data did not support catch‐up vaccination for women older than 20 years. Older adolescents who skipped routine vaccination due to the government’s suspension of its vaccine recommendation could benefit from receiving catch‐up vaccination before age 20 years.
Genetic risk score predicts risk for overweight and obesity in Finnish preadolescents
Authors: Viljakainen Heli , Dahlström Emma , Figueiredo Rejane , Sandholm Niina , Rounge Trine B. , Weiderpass Elisabete
Published: October 2019

Common genetic variants predispose to obesity with varying contribution by age. We incorporated known genetic variants into genetic risk scores (GRSs) and investigated their associations with overweight/obesity and central obesity in preadolescents. Furthermore, we compared GRSs with lifestyle factors, and tested if they predict the change in body size and shape in a 4‐year follow‐up. We utilized 1142 subjects from the Finnish Health in Teens (Fin‐HIT) cohort. Overweight and obesity were defined with age‐ and gender‐specific body mass index (BMI) z‐score (BMIz), while central obesity by the waist‐to‐height ratio (WHtR). Background data on parental language, eating habits, leisure‐time physical activity (LTPA) and sleep duration were included. Genotyping was performed with the Metabochip platform. Weighted, standardized GRSs were derived. Of the11‐year‐old children, 25.5% were at least overweight and 90.8% had Finnish speaking background. BMI‐GRS was associated with higher risk for overweight with odds ratio (95% confidence interval) of 1.39 (1.20; 1.60) and obesity 1.41 (1.08; 1.83), but not with central obesity. BMI‐GRS was weakly and inversely associated with the changes in BMIz and WHtR in the 4‐year follow‐up. Waist‐to‐hip ratio‐GRS was not related to any obesity measures at baseline nor in the follow‐up. The effect of BMI‐GRS is similar to that of low LTPA on overweight. An interaction between parental language and BMI‐GRS was noted (P = .019): BMI‐GRS associated more strongly with overweight in Swedish than in Finnish speakers. We further identified two suggestive genetic variants near LOC101926977 and LOC105369677 associated with BMIz in preadolescents which were replicated in the adult population. In preadolescents, known genetic predisposing factors induce a risk for overweight comparable to low LTPA. However, the GRS was poor in predicting short‐term changes in BMI or WHtR.
Global Imbalance Adjustment: Stylized Facts, Driving Factors and China's Prospects
Authors: Zhang Ming , Liu Yao
Published: October 2019

This paper summarizes global imbalance adjustment after the GFC and analyzes the evolution of balance of payments using a four‐quadrant diagram. We construct the framework of a stock adjustment mechanism to analyze the main driving factors for the imbalance in surplus/deficit countries and debtors/creditors in an attempt to determine the sustainability of imbalance adjustment. We find that imbalances have been reduced to some extent, but most countries have not achieved rebalance after the global financial crisis. Therefore, we propose an ideal path for global imbalance adjustment and summarize the policy practices of representative countries that have followed this route. Based on our analysis, we suggest that China should learn from the Australian experience and adopt a macro‐prudential assessment policy, actively adjust the domestic economic structure and optimize the structure of balance of payments.
Diving beetle offspring oviposited in amphibian spawn prey on the tadpoles upon hatching
Authors: Gould John , Valdez Jose W. , Clulow John , Clulow Simon
Published: October 2019

In highly ephemeral freshwater habitats, predatory vertebrates are typically unable to become established, leaving an open niche often filled by macroinvertebrate predators. However, these predators are faced with the challenge of finding sufficient food sources as the rapid rate of desiccation prevents the establishment of extended food chains and limits the number of prey species present. It could therefore be advantageous for predators to synchronize their phenology with that of their prey within sites of extreme ephemerality. We report the first case of adult diving beetles (Hydaticus parallelus) ovipositing their eggs within spawn of an amphibian species (sandpaper frog,Lechriodus fletcheri). This behavior was found among several pools used byL. fletcherifor reproduction. Beetle eggs oviposited in frog spawn were found to hatch within 24 h of the surroundingL. fletcherieggs, with the larvae becoming voracious consumers of the hatched tadpoles. Although it has yet to be established experimentally whether this is an adaptive behavior, the laying of eggs among potential future tadpole prey in this instance should confer significant fitness benefits for the offspring upon hatching, ensuring that they are provided an immediate source of food at the start of their development and potentially throughout. This oviposition behavior might be common among diving beetles and could form a significant predatory threat for amphibians with a free‐swimming larval stage in ephemeral freshwater habitats.
Imaging biomarkers of posttraumatic epileptogenesis
Authors: Garner Rachael , La Rocca Marianna , Vespa Paul , Jones Nigel , Monti Martin M. , Toga Arthur W. , Duncan Dominique
Published: October 2019

Traumatic brain injury (TBI) affects 2.5 million people annually within the United States alone, with over 300 000 severe injuries resulting in emergency room visits and hospital admissions. Severe TBI can result in long‐term disability. Posttraumatic epilepsy (PTE) is one of the most debilitating consequences of TBI, with an estimated incidence that ranges from 2% to 50% based on severity of injury. Conducting studies of PTE poses many challenges, because many subjects with TBI never develop epilepsy, and it can be more than 10 years after TBI before seizures begin. One of the unmet needs in the study of PTE is an accurate biomarker of epileptogenesis, or a panel of biomarkers, which could provide early insights into which TBI patients are most susceptible to PTE, providing an opportunity for prophylactic anticonvulsant therapy and enabling more efficient large‐scale PTE studies. Several recent reviews have provided a comprehensive overview of this subject (Neurobiol Dis, 123, 2019, 3; Neurotherapeutics, 11, 2014, 231). In this review, we describe acute and chronic imaging methods that detect biomarkers for PTE and potential mechanisms of epileptogenesis. We also describe shortcomings in current acquisition methods, analysis, and interpretation that limit ongoing investigations that may be mitigated with advancements in imaging techniques and analysis.
Non‐verbal mate retention behaviour in women and its relation to couple's relationship adjustment and satisfaction
Authors: Lindová Jitka , Klapilová Kateřina , Johnson Devin , Vobořilová Adéla , Chlápková Barbora , Havlíček Jan
Published: October 2019

The function of mate retention strategies is to preserve the bond between romantic partners and to prevent desertion, which is also why such behaviours are often elicited by the presence of a potential rival. Most existing studies on mate retention are based on self‐reports, which are prone to various biases. In this study, we observed non‐verbal behaviour of 47 long‐term romantic heterosexual couples during their interview with a female experimenter, whom the women in the couples may have perceived as a potential rival. We measured non‐verbal displays of mate retention tactics (direct guarding, intimacy inducement, appearance enhancement, and love and care display), as well as relationship maintenance strategies of openness and positivity. We expected that relationship quality as reported by both partners in the couple would be positively associated with ‘benefit‐provisioning’ mate retention behaviours and negatively associated with a ‘cost‐inflicting’ mate retention tactic (direct guarding). Relationship quality was assessed by Spanier's Dyadic Adjustment Scale using both the total score of dyadic adjustment and a Dyadic Satisfaction subscale. We found a significant association between both partners' dyadic adjustment and satisfaction and woman's appearance enhancement behaviours (such as self‐touch, hair flip and primp) in the presence of her partner and a potential rival. We also found a negative association between partner's dyadic adjustment and woman's direct guarding of partner using short looks, and a positive association between woman's intimacy‐inducing behaviour using long gaze and her own dyadic satisfaction and her partner's dyadic adjustment. Our results highlight the specific role of female attractiveness in later stages of romantic relationships within the context of mate retention and draw attention to the significance of the use of observational techniques in addition to self‐reports.
Psychopathic traits of corporate leadership as predictors of future stock returns
Authors: Omar Ayman M. A. , Wisniewski Tomasz Piotr , Yekini Liafisu Sina
Published: October 2019

This paper examines whether it is possible to forecast 1‐year‐ahead returns of individual companies based on the observed ‘psychopathic’ characteristics of their top management team. We find that language characteristic of psychopaths present in annual report narratives, questionable integrity, excessive risk‐taking, and failure to contribute to charitable undertakings tend to reduce future shareholder wealth. These findings imply that firms could benefit from incorporating psychological evaluation in their recruitment processes, especially when seeking to fill senior management posts. While the return predictability described in this paper supports the upper echelons perspective, it simultaneously challenges the notion of informationally efficient stock prices.
The combined effects of hypoxia and fish kairomones on several physiological and life history traits of Daphnia
Authors: Wilczynski Wojciech , Dynak Przemysław , Babkiewicz Ewa , Bernatowicz Piotr , Leniowski Konrad , Maszczyk Piotr
Published: October 2019

Numerous studies have tested the combined effect of the threat of predation by fish and low oxygen concentrations on the phenotypic plasticity of Daphnia. These studies assessed the trade‐off between minimising predation risk and the negative effects of oxygen deficiencies in the context of depth selection behaviour. We tested whether this trade‐off also affects physiological and life history traits. We expected an interactive effect between the threat of fish predation and low oxygen concentrations, such, that the net effect of both stressors would be antagonistic (lower than the sum of each of the stressors acting separately), rather than additive (or synergistic) on the majority of traits investigated, but we predicted synergistic effects on heat shock proteins (HSPs).

To test this, we performed life table experiments in different oxygen concentrations (normoxia and hypoxia) and levels of predation threat (the presence and absence of fish kairomones) on HSP70 and putative HSP110, haemoglobin concentration and life history traits with small‐bodied Daphnia galeata and large‐bodied Daphnia pulex originating from waterbodies where there were different risks of fish predation.

As predicted, the net effect of both stressors was antagonistic for most of the physiological and ecological variables studied. The presence of kairomones resulted in decreased body size of adults, egg size, egg size in relation to brood chamber volume, and in increased clutch size in relation to body size. These effects were weaker in hypoxia than in normoxia, which may suggest an existence of adaptive responses caused by a lower perceived risk in hypoxia than in normoxia, as the foraging abilities of fish are limited by oxygen deficiencies.

The presence of kairomones hampered the production of haemoglobin in hypoxia for the clones of larger‐bodied species, which suggests the existence of a trade‐off between reduced visibility under positive‐size selective predation risk and increased efficiency of oxygen transport to body tissues. The presence of kairomones and hypoxia resulted in an increased level of putative HSP110, and the effect of kairomones was stronger in hypoxia than in normoxia. More complex results were obtained for the effect of both stressors on the level of HSP70.

The findings of our study provide a new insight on the interactions between planktivorous fish and zooplankton in aquatic food webs. More specifically, these findings suggest the existence of unexplored size‐dependent eco‐physiological trade‐offs between minimising predation risk and mitigating the negative effects of oxygen deficiencies.
Population change in breeding boreal waterbirds in a 25‐year perspective: What characterises winners and losers?
Authors: Elmberg Johan , Arzel Celine , Gunnarsson Gunnar , Holopainen Sari , Nummi Petri , Pöysä Hannu , Sjöberg Kjell
Published: October 2019

Understanding drivers of variation and trends in biodiversity change is a general scientific challenge, but also crucial for conservation and management. Previous research shows that patterns of increase and decrease are not always consistent at different spatial scales, calling for approaches combining the latter. We here explore the idea that functional traits of species may help explaining divergent population trends.

Complementing a previous community level study, we here analyse data about breeding waterbirds on 58 wetlands in boreal Fennoscandia, covering gradients in latitude as well as trophic status. We used linear mixed models to address how change in local abundance over 25 years in 25 waterbird species are associated with life history traits, diet, distribution, breeding phenology, and habitat affinity.

Mean abundance increased in 10 species from 1990/1991 to 2016, whereas it decreased in 15 species. Local population increases were associated with species that are early breeders and have small clutches, an affinity for luxurious wetlands, an herbivorous diet, and a wide breeding range rather than a southern distribution. Local decreases, by contrast, were associated with species having large clutches and invertivorous diet, as well as being late breeders and less confined to luxurious wetlands. The three species occurring on the highest number of wetlands all decreased in mean abundance.

The fact that early breeders have done better than late fits well with previous research about adaptability to climate change, that is, response to earlier springs. We found only limited support for the idea that life history traits are good predictors of wetland level population change. Instead, diet turned out to be a strong candidate for an important driver of population change, as supported by a general decrease of invertivores and a concomitant increase of large herbivores.

In a wider perspective, future research needs to address whether population growth of large‐bodied aquatic herbivores affects abundance of co‐occurring invertivorous species, and if so, if this is due to habitat alteration, or to interference or exploitative competition.
Temperature change as a driver of spatial patterns and long‐term trends in chironomid (Insecta: Diptera) diversity
Authors: Engels Stefan , Medeiros Andrew S. , Axford Yarrow , Brooks Stephen J. , Heiri Oliver , Luoto Tomi P. , Nazarova Larisa , Porinchu David F. , Quinlan Roberto , Self Angela E.
Published: October 2019

Anthropogenic activities have led to a global decline in biodiversity, and monitoring studies indicate that both insect communities and wetland ecosystems are particularly affected. However, there is a need for long‐term data (over centennial or millennial timescales) to better understand natural community dynamics and the processes that govern the observed trends. Chironomids (Insecta: Diptera: Chironomidae) are often the most abundant insects in lake ecosystems, sensitive to environmental change, and, because their larval exoskeleton head capsules preserve well in lake sediments, they provide a unique record of insect community dynamics through time. Here, we provide the results of a metadata analysis of chironomid diversity across a range of spatial and temporal scales. First, we analyse spatial trends in chironomid diversity using Northern Hemispheric data sets overall consisting of 837 lakes. Our results indicate that in most of our data sets, summer temperature (Tjul) is strongly associated with spatial trends in modern‐day chironomid diversity. We observe a strong increase in chironomid alpha diversity with increasing Tjul in regions with present‐day Tjul between 2.5 and 14°C. In some areas with Tjul > 14°C, chironomid diversity stabilizes or declines. Second, we demonstrate that the direction and amplitude of change in alpha diversity in a compilation of subfossil chironomid records spanning the last glacial–interglacial transition (~15,000–11,000 years ago) are similar to those observed in our modern data. A compilation of Holocene records shows that during phases when the amplitude of temperature change was small, site‐specific factors had a greater influence on the chironomid fauna obscuring the chironomid diversity–temperature relationship. Our results imply expected overall chironomid diversity increases in colder regions such as the Arctic under sustained global warming, but with complex and not necessarily predictable responses for individual sites.
Increased high‐latitude photosynthetic carbon gain offset by respiration carbon loss during an anomalous warm winter to spring transition
Authors: Liu Zhihua , Kimball John S. , Parazoo Nicholas C. , Ballantyne Ashley P. , Wang Wen J. , Madani Nima , Pan Caleb G. , Watts Jennifer D. , Reichle Rolf H. , Sonnentag Oliver , Marsh Philip , Hurkuck Miriam , Helbig Manuel , Quinton William L. , Zona Donatella , Ueyama Masahito , Kobayashi Hideki , Euskirchen Eugénie S.
Published: October 2019

Arctic and boreal ecosystems play an important role in the global carbon (C) budget, and whether they act as a future net C sink or source depends on climate and environmental change. Here, we used complementary in situ measurements, model simulations, and satellite observations to investigate the net carbon dioxide (CO2) seasonal cycle and its climatic and environmental controls across Alaska and northwestern Canada during the anomalously warm winter to spring conditions of 2015 and 2016 (relative to 2010–2014). In the warm spring, we found that photosynthesis was enhanced more than respiration, leading to greater CO2 uptake. However, photosynthetic enhancement from spring warming was partially offset by greater ecosystem respiration during the preceding anomalously warm winter, resulting in nearly neutral effects on the annual net CO2 balance. Eddy covariance CO2 flux measurements showed that air temperature has a primary influence on net CO2 exchange in winter and spring, while soil moisture has a primary control on net CO2 exchange in the fall. The net CO2 exchange was generally more moisture limited in the boreal region than in the Arctic tundra. Our analysis indicates complex seasonal interactions of underlying C cycle processes in response to changing climate and hydrology that may not manifest in changes in net annual CO2 exchange. Therefore, a better understanding of the seasonal response of C cycle processes may provide important insights for predicting future carbon–climate feedbacks and their consequences on atmospheric CO2 dynamics in the northern high latitudes.
Ignatius of Loyola, Jonathan Edwards, and Indifference
Authors: Kearney John
Published: October 2019

The aim of this paper is threefold: First, I provide a brief account of Ignatian indifference as contained in the Spiritual Exercises. I distinguish between two senses of ‘indifference’ and apply them to an imaginary Regina who is faced with the decision about whether to give an inheritance to UNICEF or use the funds to finance her daughter’s college education. Second, I argue that Jonathan Edwards’s polemic, in Freedom of the Will, against Isaac Watts’s account of indifference, is open to the ‘straw man objection’ when applied to the Ignatian concept. Finally, I put forth a Kantian based critique of Ignatian indifference. I claim that while indifference is a logically consistent notion it may very well be psychologically problematic. If it is an open question whether Regina can ever know with certainty that she has acted from the pure motive of duty, then it is also an open question whether she can ‘find’ herself indifferent in the Ignatian senses of the term.
A new matrikine‐derived peptide up‐regulates longevity genes for improving extracellular matrix architecture and connections of dermal cell with its matrix
Authors: Leroux R. , Ringenbach C. , Marchand T. , Peschard O. , Mondon P. , Criton P.
Published: October 2019

Objective

Skin extracellular matrix (ECM) is a dense and well‐organized structure produced by fibroblasts. This ECM transduces environmental mechano‐signals to cell nucleus through the integrin–actin complex, thus triggering ECM protein syntheses. The aim of this study was to discover a novel peptide, structurally related to dermal matrikines, that promotes syntheses of ECM components.

Methods and results

Screening tests with 120 peptides were carried out by using normal dermal human fibroblasts (HF). As a result, one candidate of interest was isolated, the N‐Prolyl Palmitoyl Tripeptide‐56 Acetate (PP56), which increases collagen and fibronectin productions at gene and/or protein levels. Using liquid chromatography–tandem mass spectrometry (LC‐MS/MS), a recent and innovative analytical technology, in addition to more traditional techniques, it was showed that two metabolic pathways were significantly modulated: one for collagen production and one for actin. Moreover, this peptide up‐regulated the transcription of Forkhead Box O (FOXO) and sestrin messenger RNAs (mRNA), leading to production of proteins involved into longevity and more recently in collagen production.

Results

Results indicated that this peptide is a potential candidate to improve ECM density and organization in a new way.
EXPLORING THE CONSISTENCY OF HIGHER ORDER RISK PREFERENCES
Authors: Haering Alexander , Heinrich Timo , Mayrhofer Thomas
Published: October 2019

This study measures higher order risk preferences and their consistency. We explore the role of country differences, the variation of stakes, and the framing of lotteries. We observe a robust dichotomous pattern of choice behavior in China, the United States, and Germany. The majority of choices are consistent with mixed risk aversion or mixed risk‐loving behavior. We also find this pattern after a 10‐fold increase in the stakes. Finally, our results reveal that this pattern is strengthened if the lotteries are displayed in compound instead of reduced form. In a follow‐up study, we explore potential explanations for this framing effect.
Therapeutic drug monitoring in inflammatory bowel disease reduces unnecessary use of infliximab with substantial associated cost‐savings
Authors: Wu Yang , Lin Brian , Thilakanathan Cynthuja , Lehmann Patritica , Xuan Wei , Mohsen Waled , Toong Catherine , Williams Astrid‐Jane , Ng Watson , Connor Susan
Published: October 2019

Background

Therapeutic drug monitoring (TDM) of infliximab (IFX) levels in inflammatory bowel disease (IBD) patients can help to guide dose adjustments or changes to therapy for selected patients in remission or with secondary loss of response (LOR).

Aims

To determine how IFX TDM is utilised in a real‐life clinical setting and to quantify the potential for TDM to reduce the unnecessary use of IFX.

Methods

Data from all public IBD IFX level testing performed across Australia were prospectively collected from June 2016 to July 2017 to assess physician‐reported for testing indications (induction, in remission or LOR) and associated results. The hypothetical influence of IFX TDM was based on an optimal therapeutic range of 6–10 mg/L for mucosal healing.

Results

Secondary LOR (reactive TDM) was the most common indication for TDM. These patients have consistently lower median IFX levels: 3.02 mg/L (IQR 1.14–6.67 mg/L) versus 5.22 mg/L (IQR 2.70–8.12 mg/L), P = 0.0001 compared with patients in remission (proactive TDM). TDM helped to identify unnecessary use of IFX in 30.6% of the TDM tests performed in luminal Crohn disease and ulcerative colitis patients, with an associated drug cost saving of $531.38 per IFX TDM test episode. Unnecessary IFX use was identified in 38.9% (96/247) of reactive IFX TDM tests performed and in 19.3% (35/181) of proactive testing.

Conclusion

Use of both reactive and proactive IFX TDM is cost‐effective for IBD management as it informs the clinician where unnecessary use of IFX can be stopped.
Respiratory acute discharge service: a hospital in the home programme for chronic obstructive pulmonary disease exacerbations (RADS study)
Authors: Samaranayake Chinthaka B. , Neill Jane , Bint Michael
Published: October 2019

Background

Respiratory Acute Discharge Service (RADS) is a novel early discharge service with nurse‐led community based recovery in selected patients with acute exacerbations of chronic obstructive pulmonary disease.

Aim

This pilot study aimed to determine the efficacy and safety of the programme in an Australian tertiary hospital.

Methods

All patients who were recruited to RADS at Sunshine Coast University Hospital over a 6 months period from June to November 2018 were included. The co‐primary outcomes were length of hospital days saved and rate of readmission within 30 days from discharge.

Results

A total of 166 patients (median age 74 years (interquartile range 70–80 years)) was recruited to the programme over the study period. The mean forced expiratory volume in one second (FEV1%) of the patients was 42% (standard deviation 19). The median length‐of‐stay prior to discharge on the RADS programme was 1 day (range 0–5), compared to a previous average of 5.8 days in our health service. Patients were on the programme for a median of 4 days (range 1–6). A total of 613 hospital bed days was saved over the study period, with significant cost savings. Forty‐one (24.7%) patients represented to hospital within 30 days, the majority (64%) were due to recurrent symptoms. The rate of 30‐day all‐cause mortality for the study population was 1 (0.6%).

Conclusion

Early supported discharge care model with nurse‐led community based recovery after an acute exacerbation of chronic obstructive pulmonary disease in selected patients is safe, and has the potential to provide greater flow through the hospital systems with cost effective care.
Approaches to use the WHO respiratory syncytial virus surveillance platform to estimate disease burden
Authors: Pebody Richard , Moyes Jocelyn , Hirve Siddhivinayak , Campbell Harry , Jackson Sandra , Moen Ann , Nair Harish , Simões Eric A. F. , Smith Peter G. , Wairagkar Niteen , Zhang Wenqing
Published: October 2019

The World Health Organization (WHO) recently completed the first phase of a RSV surveillance pilot study in fourteen countries (two to three in each WHO region) building on the Global Influenza Surveillance and Response System (GISRS). This active surveillance strategy had several objectives including understanding RSV‐related health burden in a variety of settings. A range of approaches can be used to estimate disease burden; most approaches could not be applied by participating countries in the WHO surveillance pilot. This article provides the recommendations made by WHO for strengthening and expanding the scope of the RSV surveillance in the next phase to enable burden estimation.
Long‐term clinical outcomes from real‐world experience of left atrial appendage exclusion with LARIAT device
Authors: Parikh Valay , Bartus Krzysztof , Litwinowicz Radoslaw , Turagam Mohit K. , Sadowski Jerzy , Kapelak Boguslaw , Bartus Magdalena , Podolec Jakub , Brzezinski Maciej , Musat Dan , Rasekh Abdi , Mittal Suneet , Cheng Jie , Badhwar Nitish , Lee Randall , Lakkireddy Dhanunjaya
Published: October 2019

Background

Left atrial appendage closure (LAAC) with LARIAT has emerged as one of the alternatives to oral anticoagulation (OAC) in patients with nonvalvular atrial fibrillation (AF). Our aim was to study long‐term outcomes in patients undergoing LARIAT procedure.

Methods

We analyzed patients screened for LARIAT device in four centers between December 2009 and June 2012. Out of these, patients who didn't undergo LAAC with the LARIAT device due to unfavorable LAA morphology and other preprocedural contraindications were included in control group. We analyzed thromboembolism, bleeding events, and mortality between LAA and control group.

Results

About 153 patients were screened. Out of these, 108 (70.6%) patients underwent LARIAT placement (LAA arm) and 45 (29.4%) excluded patients were included in control arm. There were no differences in CHADS2 and CHA2DS2‐VASc score. Mean HAS‐BLED score was significantly higher in the LARIAT group (3.5 ± 1.06 vs 3.09 ± 1.22, P = .04). Mean follow‐up time (in years) was 6.56 ± 0.84 in LAA and 6.5 ± 1.26 in control arm. During follow‐up period, the LARIAT group was associated with significantly less thromboembolic events (1.9% vs 24%, P < .001), bleeding events (9.2% vs 24.4%, P = .03), and mortality (5.6% vs 20%, P = .01) as compared with the control group.

Conclusions

Long‐term data from routine clinical practice from our study suggests that LAA exclusion with LARIAT device is an effective treatment in management of nonvalvular AF patients with high risk of stroke, bleeding, and mortality. Further randomized trials, such as aMAZE, will provide more insight in this expanding field.
The characteristics and risk factors of hepatocellular carcinoma in nonalcoholic fatty liver disease without cirrhosis
Authors: Tobari Maki , Hashimoto Etsuko , Taniai Makiko , Kodama Kazuhisa , Kogiso Tomomi , Tokushige Katsutoshi , Yamamoto Masakazu , Takayoshi Nishino , Satoshi Katagiri , Tatsuo Araida
Published: October 2019

Background and Aim

We evaluated the characteristics of hepatocellular carcinoma (HCC) in patients who had non‐alcoholic fatty liver disease (NAFLD) without cirrhosis.

Methods

We prospectively followed NAFLD patients at our University hospital. NAFLD was diagnosed from detection of steatosis by histology or imaging, no alcohol intake, and exclusion of other liver diseases. Cirrhosis was defined by histological features, imaging data, and symptoms. We compared NAFLD‐related HCC with or without cirrhosis and non‐cirrhotic NAFLD with or without HCC.

Results

There were 48 non‐cirrhotic HCC patients and 71 cirrhotic HCC patients. Multiple logistic regression analysis revealed that other than liver function factors, male gender (OR: 5.603, 95%CI: 1.577–19.900), light drinker (OR: 2.797, 95%CI: 1.031–7.589), and tumor size (OR: 1.031, 95%CI 1.009–1.055) differ significantly between these two groups. The recurrence rate was significantly lower in the non‐cirrhotic HCC group than the cirrhotic HCC group, with risk factors being des‐γ‐carboxy prothrombin and the number of HCCs. The non‐cirrhotic HCC group showed significantly better survival because of absence of non‐cancerous liver failure. Comparison between non‐cirrhotic NAFLD patients with or without HCC (n = 612) revealed the following risk factors for HCC: male gender (OR: 7.774, 95%CI: 2.176–27.775), light drinker (OR: 4.893, 95%CI: 1.923–12.449), and high FIB4 index (OR 2.634, 95%CI: 1.787–3.884).

Conclusion

In patients with non‐cirrhotic NAFLD, important risk factors for HCC were male gender, alcohol consumption, and the FIB4 index. HCC recurrence and survival were only influenced by the tumor stage. We should be aware of alcohol consumption as a modifiable risk factor for HCC.
Association of amniotic fluid sludge with preterm labor and histologic chorioamnionitis in pregnant Japanese women with intact membranes: A retrospective study
Authors: Yasuda Shun , Tanaka Masayo , Kyozuka Hyo , Suzuki Satoshi , Yamaguchi Akiko , Nomura Yasuhisa , Fujimori Keiya
Published: October 2019

Aim

The presence of amniotic fluid sludge has been identified as a risk factor for preterm birth. We sought to validate the clinical characteristics of amniotic fluid sludge in Japanese pregnant women with preterm labor and intact membranes.

Methods

This was a retrospective study of 54 patients. The presence of amniotic fluid sludge was confirmed using transvaginal ultrasonography data during pregnancy. The following data were collected: gestational age, the presence of histologic chorioamnionitis, time from the diagnosis of threatened premature labor to delivery, oncofetal fibronectin (onfFN) levels, C‐reactive protein peak value levels, cervical length at the time of onset of threatened premature labor and types of neonatal complications.

Results

Significant differences (P = 0.03) were observed in the age at delivery in relation to the presence of amniotic sludge: delivery occurred at 28.3 ± 4.5 weeks and 31.7 ± 4.3 weeks in sludge positive patients and sludge‐negative patients, respectively. Presence of sludge in patients diagnosed with histological chorioamnionitis at <37 weeks of gestation differed significantly (P = 0.01): sludge‐positive, 81.8%; sludge‐negative, 20.9%. Among the sludge‐positive patients, 100% were positive for serum onfFN (≥50 ng/mL), whereas only 54% of sludge‐negative patients were positive for serum onfFN (P = 0.03). Presence of amniotic fluid sludge did not significantly affect neonatal complications.

Conclusion

Our results confirmed previous findings that amniotic fluid sludge is a self‐determining risk factor for preterm birth and chorioamnionitis in pregnant Japanese women.
Phenolic compounds from nutmeg (Myristica fragrans Houtt.) inhibit the endocannabinoid-modulating enzyme fatty acid amide hydrolase
Authors: El-Alfy Abir T , Abourashed Ehab A , Patel Christina , Mazhari Nunmoula , An HeaRe , Jeon Andrew
Published: October 2019

Objectives

The study aimed to identify nutmeg compounds that indirectly interact with the endocannabinoid system through inhibition of the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) enzymes.

Methods

Thirteen compounds were screened for FAAH and MAGL inhibition. Compounds demonstrating significant FAAH inhibition were evaluated to determine the halfmaximal inhibitory concentration (IC50). The most potent compound was investigated in the elevated plus maze (EPM) rodent anxiety model.

Key findings

Three compounds, licarin A (9), 5′-methoxylicarin A (8) and malabaricone C (6) were most active in inhibiting FAAH with IC50 of 7.02 μm ± 2.02, 4.57 μm ± 0.66 and 38.29 μm ± 6.18, respectively. None of the purified compounds showed significant MAGL inhibition. Because of its relative high potency and selectivity, compound 8 was further evaluated in the EPM animal model of anxiety. The compound showed significant increase in number of open arm entries (P < 0.05) when administered at 120 mg/kg dose. No effect was observed on the locomotor activity.

Conclusions

Results collected introduce active nutmeg compounds as potential leads for further development. Of the three compounds, 8 possesses highest potency and FAAH selectivity as well as anxiolytic activity. Furthermore, in vivo testing in appropriate behavioural animal paradigms is warranted.
Genetic diversity of Cedrela fissilis (Meliaceae) in the Brazilian Atlantic Forest reveals a complex phylogeographic history driven by Quaternary climatic fluctuations
Authors: Mangaravite Érica , da Silveira Thamyres C. , Huamán‐Mera Alexander , de Oliveira Luiz O. , Muellner‐Riehl Alexandra N. , Schnitzler Jan
Published: October 2019

Quaternary climatic fluctuations have shaped the geographic distribution of lineages, potentially affecting the demography, genetic structure, and patterns of genetic diversity of extant species. Different phylogeographic scenarios have been proposed for plants in neotropical cloud forests during the Last Glacial Maximum based on paleoecological data: the dry refugia hypothesis (DRH) and the moist forest hypothesis. We specifically focus on the Brazilian Atlantic Forest (BAF) range of Cedrela fissilis (Meliaceae), sampling 410 specimens from 50 localities. Our study combines analyses of the genetic diversity, phylogeographic patterns, and past geographic distributions with a particular focus on highland populations. We identified 283 alleles across the 11 microsatellite loci, ranging from 18 to 33 alleles per locus, distributed across five genetic groups. Most populations of C. fissilis from the BAF exhibited a diffuse genetic structure, reflected in low pairwise FST values, which could be the consequence of high gene flow. In addition, the plastid data showed a connection between the western, southern, and eastern populations in the North‐East of Brazil, but no association between genetic data and elevation was observed. Habitat suitability projections over the past 140 000 years showed less fragmentation relative to the present, indicating a higher connectivity and gene flow. Our results provide support for both the moist forest as well as the DRH, suggesting that most likely, a mixture of these processes has acted through space and time.