bluuebunny/crossref_metadata_2025 huggingface dataset:
System Performance Implications of Capacity and Flexibility Constraints on Bullwhip Effect in Supply Chains
Authors: Narayanan Arunachalam , Mackelprang Alan W. , Malhotra Manoj K.
Published: May 2021

Utilizing behavioral experiments involving approximately one thousand subjects, we empirically evaluate the relationship between volume flexibility and the Bullwhip Effect (BWE). We not only evaluate differences in the level of BWE, but also differences in associated system performance. We find that systems with hard capacity constraints are effective at limiting BWE, but also produce very poor customer service levels. However, systems with low levels of volume flexibility generate similar performance as fully flexible systems but do so while also generating a lower BWE. In a multi‐echelon setting, we show that having partial volume flexibility at the upstream echelon helps in reducing order variance, with no significant drop in service level in the supply chain. This is particularly useful in those manufacturing environments which prefer stable orders for production planning without affecting the downstream customer service level. Counterintuitively, both experiments uncovered instances of irrational behavior where participants invoked flexibility in ways that did not always enhance system performance. In addition, these experiments also established enhancements in BWE and system performance through introduction of incremental volume flexibility into upstream echelon of a supply chain.
Bearing witness against unbearable whiteness: Lessons from Luther for confronting racism today
Authors: Bateza Anthony
Published: May 2021

Anti‐black racism has a long history in the United States, and while its presence is constant its ramifications are manifold. This means that careful attention, prudent discernment, and diligent action are required if we are to confront racism today. In this article I examine the obstacles that whiteness creates when it comes to recognizing the testimony of Black people. My claim is that white peoples in general, and Lutherans in particular, suffer from either a persistent inability or cultivated unwillingness to receive Black witness. I begin by briefly discussing Martin Luther's views on bearing witness, highlighting the theological and practical importance of this work within a Lutheran theological heritage. Next, I proceed to the ways that witness is compromised, the conditions that undermine the giving and receiving of testimony. Drawing on insights from Rebecca Kukla, Miranda Fricker, and others, I frame these compromises as instances of discursive and epistemic injustice, as harms done to Black subjects as their white counterparts fail to take up offerings of truth and extend trust. Finally, I conclude by suggesting some Lutheran theological and practical opportunities for resistance and retraining, so that anti‐racist work might be embodied more fully in spaces filled with whiteness.
Long‐term incidence of hypoglycaemia‐related events after bariatric surgery or usual care in the Swedish Obese Subjects study: A register‐based analysis
Authors: Sjöholm Kajsa , Jacobson Peter , Taube Magdalena , Svensson Per‐Arne , Andersson Assarsson Johanna C. , Carlsson Lena M. S. , Peltonen Markku
Published: May 2021

Aims

To examine the incidence of hypoglycaemia‐related events over a period of up to 31 years in patients treated with bariatric surgery in the prospective, controlled Swedish Obese Subjects (SOS) study.

Materials and Methods

The SOS study (n = 4047) is a prospective controlled intervention study. The present analysis included 1989 patients treated with bariatric surgery and 2027 control patients with obesity who received usual care. Diagnosed hypoglycaemia and events commonly attributed to hypoglycaemia (confusion, syncope, epilepsy and seizures), requiring hospital or specialist outpatient treatment, were identified by searching the National Patient Register. Analyses were stratified by baseline glycaemic status. Hazard ratios were adjusted for inclusion year, age, sex, smoking, glycated haemoglobin (HbA1c) level and body mass index at baseline. At the time of analysis (December 31, 2018), the median follow‐up was 22 years.

Results

Compared with usual care, bariatric surgery was associated with increased incidence of hypoglycaemia‐related events in patients without baseline diabetes (168 and 219 events, respectively; log‐rank P = .011), with a more pronounced risk during the first years of follow‐up (test of time‐treatment interaction P = .010). Multivariate analyses in patients without baseline diabetes indicated that male sex (P < .001), older age (P = .001) and higher HbA1c levels (P = .006) were associated with hypoglycaemia‐related events. No association was found between risk of hypoglycaemia‐related events and bariatric surgery in patients with baseline diabetes.

Conclusions

Bariatric surgery is associated with an increased incidence of hypoglycaemia‐related events in patients without baseline diabetes, especially during the first years after treatment.
Do sodium‐glucose co‐transporter‐2 inhibitors increase plasma glucagon by direct actions on the alpha cell? And does the increase matter for the associated increase in endogenous glucose production?
Authors: Kuhre Rune E. , Deacon Carolyn F. , Wewer Albrechtsen Nicolai J. , Holst Jens J.
Published: May 2021

Sodium‐glucose co‐transporter‐2 inhibitors (SGLT2is) lower blood glucose and are used for treatment of type 2 diabetes. However, SGLT2is have been associated with increases in endogenous glucose production (EGP) by mechanisms that have been proposed to result from SGLT2i‐mediated increases in circulating glucagon concentrations, but the relative importance of this effect is debated, and mechanisms possibly coupling SGLT2is to increased plasma glucagon are unclear. A direct effect on alpha‐cell activity has been proposed, but data on alpha‐cell SGLT2 expression are inconsistent, and studies investigating the direct effects of SGLT2 inhibition on glucagon secretion are conflicting. By contrast, alpha‐cell sodium‐glucose co‐transporter‐1 (SGLT1) expression has been found more consistently and appears to be more prominent, pointing to an underappreciated role for this transporter. Nevertheless, the selectivity of most SGLT2is does not support interference with SGLT1 during therapy. Paracrine effects mediated by secretion of glucagonotropic/static molecules from beta and/or delta cells have also been suggested to be involved in SGLT2i‐induced increase in plasma glucagon, but studies are few and arrive at different conclusions. It is also possible that the effect on glucagon is secondary to drug‐induced increases in urinary glucose excretion and lowering of blood glucose, as shown in experiments with glucose clamping where SGLT2i‐associated increases in plasma glucagon are prevented. However, regardless of the mechanisms involved, the current balance of evidence does not support that SGLT2 plays a crucial role for alpha‐cell physiology or that SGLT2i‐induced glucagon secretion is important for the associated increased EGP, particularly because the increase in EGP occurs before any rise in plasma glucagon.
Real‐world performance of the MiniMed™ 670G system in Europe
Authors: Da Silva Julien , Bosi Emanuele , Jendle Johan , Arrieta Arcelia , Castaneda Javier , Grossman Benyamin , Cordero Toni L. , Shin John , Cohen Ohad
Published: May 2021

Aim

To evaluate the real‐world performance of the MiniMed 670G system in Europe, in individuals with diabetes.

Materials and Methods

Data uploaded from October 2018 to July 2020 by individuals living in Europe were aggregated and retrospectively analysed. The mean glucose management indicator (GMI), percentage of time spent within (TIR), below (TBR) and above (TAR) glycaemic ranges, system use and insulin consumed in users with 10 or more days of sensor glucose data after initial Auto Mode start were determined. Another analysis based on suboptimally (GMI > 8.0%) and well‐controlled (GMI < 7.0%) glycaemia pre‐Auto Mode initiation was also performed.

Results

Users (N = 14 899) spent a mean of 81.4% of the time in Auto Mode and achieved a mean GMI of 7.0% ± 0.4%, TIR of 72.0% ± 9.7%, TBR less than 3.9 mmol/L of 2.4% ± 2.1% and TAR more than 10 mmol/L of 25.7% ± 10%, after initiating Auto Mode. When compared with pre‐Auto Mode initiation, GMI was reduced by 0.3% ± 0.4% and TIR increased by 9.6% ± 9.9% (P < .0001 for both). Significantly improved glycaemic control was observed irrespective of pre‐Auto Mode GMI levels of less than 7.0% or of more than 8.0%. While the total daily dose of insulin increased for both groups, a greater increase was observed in the latter, an increase primarily due to increased basal insulin delivery. By contrast, basal insulin decreased slightly in well‐controlled users.

Conclusions

Most MiniMed 670G system users in Europe achieved TIR more than 70% and GMI less than 7% while minimizing hypoglycaemia, in a real‐world environment. These international consensus‐met outcomes were enabled by automated insulin delivery meeting real‐time insulin requirements adapted to each individual user.
The effects of psychological stress on approach tendencies for smoking‐related cues in smokers
Authors: Zlomuzica Armin , Lange Miriam , Reher Sarah , Machulska Alla , Rinck Mike
Published: May 2021

Stress may potentiate the chronification of nicotine addiction, but the exact mechanisms remain elusive. We performed an explorative pilot study examining the effects of psychological stress, administered via the socially evaluated cold pressor task (SECPT), on implicit approach bias for smoking‐related cues in smokers in the approach–avoidance task (AAT). Smokers (N = 24) were subjected to the stress or control condition of the SECPT by using a within‐subject design. Consistent with previous findings, a strong approach bias for smoking‐related cues in the AAT was found in smokers. Exposure to stress did not affect the general bias for smoking‐related cues in the AAT relative to the control condition of the SECPT. In additional explorative analyses, an interaction among carbon monoxide (CO) levels in expired air, cortisol levels, and stress on approach bias for smoking‐related cues was found. Higher CO levels, possibly due to recent smoking, prior to stress exposure were associated with an approach bias for smoking‐related cues. Our results suggest that CO levels in interaction with stress can modulate implicit, automatic processing in the context of nicotine addiction. Our findings might provide novel cues to how stress influences cigarette craving and smoking behavior.
Scale‐dependent effects of niche specialisation: The disconnect between individual and species ranges
Authors: Huang Shan , Tucker Marlee A. , Hertel Anne G. , Eyres Alison , Albrecht Jörg
Published: May 2021

One of the most general expectations of species range dynamics is that widespread species tend to have broader niches. However, it remains unclear how this relationship is expressed at different levels of biological organisation, which involve potentially distinctive processes operating at different spatial and temporal scales. Here, we show that range sizes of terrestrial non‐volant mammals at the individual and species level show contrasting relationships with two ecological niche dimensions: diet and habitat breadth. While average individual home range size appears to be mainly shaped by the interplay of diet niche breadth and body mass, species geographical range size is primarily related to habitat niche breadth but not to diet niche breadth. Our findings suggest that individual home range size is shaped by the trade‐off between energetic requirements, movement capacity and trophic specialisation, whereas species geographical range size is related to the ability to persist under various environmental conditions.
Rheumatoid meningitis: A systematic review and meta‐analysis
Authors: Villa Eduardo , Sarquis Teresita , de Grazia José , Núñez René , Alarcón Pablo , Villegas Rodrigo , Guevara Carlos
Published: May 2021

Background and purpose

Rheumatoid meningitis (RM) is a neurological complication of rheumatoid arthritis (RA). Current evidence is based on case reports and partial reviews.

Methods

This is a systematic review and meta‐analysis following the PRISMA statement. The aim is to describe the characteristics of the disease, including clinical, imaging and laboratory findings, treatment, outcomes and prognosis reported in the literature.

Results

In all, 103 studies with 130 cases were included. RM affected adults with an average age of 62 years, with or without a previous RA diagnosis. RA activity and time with the disease were associated with a worse prognosis. Most common clinical manifestations were transient focal neurological signs (64.6%), systemic symptoms (51.3%), episodic headache (50.4%) and neuropsychiatric alterations (47.7%). Joint manifestations were present in only 27.4% of cases. Brain magnetic resonance imaging showed unilateral or bilateral involvement, predominantly frontoparietal. Both pachymeninges and leptomeninges were affected, the latter more frequently (82.88%). The laboratory findings included increased levels of rheumatoid factor (89.71%), anti‐cyclic citrullinated peptide (89.47%), C‐reactive protein (82.54%) and erythrocyte sedimentation rate (81.81%). Cerebrospinal fluid analysis showed an increase in the protein level (76.14%), with pleocytosis (85.19%) of mononuclear predominance (89.19%). Biopsy was performed in 72.52% of the patients. Corticosteroid pulse therapy was the main induction therapy. Disease relapse occurred in 31.17% of patients, whilst 54.54% had a full recovery.

Conclusions

Rheumatoid meningitis must be considered in adult patients with or without RA diagnosis, high‐dose corticosteroid induction therapy should be installed and maintenance therapy plays a key role. It is not recommended to use anti‐TNF as an induction therapy. Nowadays, RM has a significantly better outcome. These findings may aid clinicians in timely RM diagnosis and treatment, thus improving its outcomes.
Innate and learned predator recognition across populations of Atlantic salmon, Salmo salar
Authors: Lau Malcolm J. , Wilson Chris C. , Neff Bryan D.
Published: May 2021

Innate and learned anti‐predator responses can be important determinants of survival in natural environments. Our study measured innate and learned anti‐predator responses in three populations of Atlantic salmon, Salmo salar. Across populations, we found that the presence of a chemical alarm cue derived from the skin of conspecifics was associated with a significant decline in behavioural activity, indicating an innate anti‐predator response to the chemical alarm cue. The presence of a kingfisher model was not associated with a change in behavioural activity, indicating that this visual predator cue does not elicit an innate anti‐predator response. Following training in which the alarm cue and predator cue were paired, the presence of a kingfisher model was not associated with a change in behavioural activity, indicating the absence of a learned anti‐predator response across the three populations. Understanding population variability in anti‐predator behaviour may be important when selecting populations for reintroduction efforts of Atlantic salmon.
Border procedures in the Commission’s New Pact on Migration and Asylum: A case of politics outplaying rationality?
Authors: Cornelisse Galina , Reneman Marcelle
Published: May 2021

This article demonstrates that the role of the European Commission in the area of asylum policy is characterised by an imbalance between politicisation and rationality. Politicisation of the role of the Commission is especially visible in its proposals for border procedures in the New Pact on Migration and Asylum. We show that the efficiency and effectiveness of these proposals are not supported by evidence or a thorough assessment of past EU action, as required by Better Regulation. The result is that they fail to address the structural problems that exist with regard to the implementation and application of EU law at external borders. The broken balance between politicisation and rationality in the legislative process leads to a prioritisation of security over freedom and justice. We argue that it needs to be compensated by a stronger role of the judiciary.
The genome of the Pyrenean desman and the effects of bottlenecks and inbreeding on the genomic landscape of an endangered species
Authors: Escoda Lídia , Castresana Jose
Published: May 2021

The Pyrenean desman (Galemys pyrenaicus) is a small semiaquatic mammal endemic to the Iberian Peninsula. Despite its limited range, this species presents a strong genetic structure due to past isolation in glacial refugia and subsequent bottlenecks. Additionally, some populations are highly fragmented today as a consequence of river barriers, causing substantial levels of inbreeding. These features make the Pyrenean desman a unique model in which to study the genomic footprints of differentiation, bottlenecks and extreme isolation in an endangered species. To understand these processes, the complete genome of the Pyrenean desman was sequenced and assembled using a Bloom filter‐based approach. An analysis of the 1.83 Gb reference genome and the sequencing of five additional individuals from different evolutionary units allowed us to detect its main genomic characteristics. The population differentiation of the species was reflected in highly distinctive demographic trajectories. In addition, a severe population bottleneck during the postglacial recolonization of the eastern Pyrenees created one of the lowest genomic heterozygosity values recorded in a mammal. Moreover, isolation and inbreeding gave rise to a high proportion of runs of homozygosity (ROH). Despite these extremely low levels of genetic diversity, two key multigene families from an eco‐evolutionary perspective, the major histocompatibility complex and olfactory receptor genes, showed heterozygosity excess in the majority of individuals, revealing that functional diversity can be maintained up to a certain extent. Furthermore, these two classes of genes were significantly less abundant than expected within ROH. In conclusion, the genomic landscape of each analysed Pyrenean desman turned out to be strikingly distinctive and was a clear reflection of its recent ancestry and current conservation conditions. These results may help characterize the genomic health of each individual, and can be crucial for the conservation and management of the species.
Geographic proximity and price efficiency: Evidence from high‐speed railway connections between firms and financial centers
Authors: Gao Hao , Qu Yuanyu , Shen Tao
Published: May 2021

We study how geographic proximity to financial centers affects price efficiency. Using high‐speed railway connections between firm cities and their nearest financial centers in China as exogenous shocks, we find stocks of connected firms are more efficiently priced than those of firms that are not connected. Consistent with our hypothesis, ease of travel has a stronger effect on firms that are closer to financial centers, smaller, have less institutional ownership and financial analyst coverage, and are not on the short sales list. Our paper highlights the importance of the geographic proximity of firms to financial centers on financial market efficiency.
The effectiveness of Shark‐Management‐Alert‐in‐Real‐Time (SMART) drumlines as a tool for catching white sharks, Carcharodon carcharias, off coastal New South Wales, Australia
Authors: Tate Rick D. , Kelaher Brendan P. , Brand Craig P. , Cullis Brian R. , Gallen Christopher R. , Smith Stephen D.A. , Butcher Paul A.
Published: May 2021

White (Carcharodon carcharias L.), bull (Carcharhinus leucas, Müller & Henle) and tiger (Galeocerdo cuvier, Péron & Lesueur) sharks are the primary species responsible for unprovoked shark bites. Historically, management practices were based on culling “target” shark species (i.e. white, bull and tiger sharks), which resulted in high levels of bycatch and mortality. Shark‐Management‐Alert‐in‐Real‐Time (SMART) drumlines were trialled in New South Wales, Australia, aiming to optimise the capture of target shark species while minimising bycatch and mortality. Target shark species accounted for 70% of the total catch, with white sharks contributing 298 of the 350 sharks that were caught. Four animals died, and bycatch consisted of 13 species including two threatened species. Generalised linear mixed models (GLMMs) revealed a significant spatial, temporal, environmental and gear influence on white shark catch rates. SMART drumlines are a useful tool for catching target shark species with low bycatch and mortality relative to historical bather protection methods.
Lender of last resort, buyer of last resort, and a fear of fire sales in the sovereign bond market*
Authors: Acharya Viral , Pierret Diane , Steffen Sascha
Published: May 2021

We document the mechanism through which the risk of fire sales in the sovereign bond market contributed to the effectiveness of two major central bank interventions designed to restore financial stability during the European sovereign debt crisis. As a lender of last resort via the long‐term refinancing operations (LTROs), the European Central Bank (ECB) improved the collateral value of sovereign bonds of peripheral countries. This resulted in an elevated concentration of these bonds in the portfolios of domestic banks, increasing fire‐sale risk and making both banks and sovereign bonds riskier. In contrast, the ECB's announcement of being a potential buyer of last resort via the Outright Monetary Transaction (OMT) program attracted new investors and reduced fire‐sale risk in the sovereign bond market.
Is the southern crab Halicarcinus planatus (Fabricius, 1775) the next invader of Antarctica?
Authors: López‐Farrán Zambra , Guillaumot Charlène , Vargas‐Chacoff Luis , Paschke Kurt , Dulière Valérie , Danis Bruno , Poulin Elie , Saucède Thomas , Waters Jonathan , Gérard Karin
Published: May 2021

The potential for biological colonization of Antarctic shores is an increasingly important topic in the context of anthropogenic warming. Successful Antarctic invasions to date have been recorded exclusively from terrestrial habitats. While non‐native marine species such as crabs, mussels and tunicates have already been reported from Antarctic coasts, none have as yet established there. Among the potential marine invaders of Antarctic shallow waters is Halicarcinus planatus (Fabricius, 1775), a crab with a circum‐Subantarctic distribution and substantial larval dispersal capacity. An ovigerous female of this species was found in shallow waters of Deception Island, South Shetland Islands in 2010. A combination of physiological experiments and ecological modelling was used to assess the potential niche of H. planatus and estimate its future southward boundaries under climate change scenarios. We show that H. planatus has a minimum thermal limit of 1°C, and that its current distribution (assessed by sampling and niche modelling) is physiologically restricted to the Subantarctic region. While this species is presently unable to survive in Antarctica, future warming under both ‘strong mitigation’ and ‘no mitigation’ greenhouse gas emission scenarios will favour its niche expansion to the Western Antarctic Peninsula (WAP) by 2100. Future human activity also has potential to increase the probability of anthropogenic translocation of this species into Antarctic ecosystems.
Oyster biomineralization under ocean acidification: From genes to shell
Authors: Chandra Rajan Kanmani , Meng Yuan , Yu Ziniu , Roberts Steven B. , Vengatesen Thiyagarajan
Published: May 2021

Biomineralization is one of the key processes that is notably affected in marine calcifiers such as oysters under ocean acidification (OA). Understanding molecular changes in the biomineralization process under OA and its heritability, therefore, is key to developing conservation strategies for protecting ecologically and economically important oyster species. To do this, in this study, we have explicitly chosen the tissue involved in biomineralization (mantle) of an estuarine commercial oyster species, Crassostrea hongkongensis. The primary aim of this study is to understand the influence of DNA methylation over gene expression of mantle tissue under decreased ~pH 7.4, a proxy of OA, and to extrapolate if these molecular changes can be observed in the product of biomineralization—the shell. We grew early juvenile C. hongkongensis, under decreased ~pH 7.4 and control ~pH 8.0 over 4.5 months and studied OA‐induced DNA methylation and gene expression patterns along with shell properties such as microstructure, crystal orientation and hardness. The population of oysters used in this study was found to be moderately resilient to OA at the end of the experiment. The expression of key biomineralization‐related genes such as carbonic anhydrase and alkaline phosphatase remained unaffected; thus, the mechanical properties of the shell (shell growth rate, hardness and crystal orientation) were also maintained without any significant difference between control and OA conditions with signs of severe dissolution. In addition, this study makes three major conclusions: (1) higher expression of Ca2+ binding/signalling‐related genes in the mantle plays a key role in maintaining biomineralization under OA; (2) DNA methylation changes occur in response to OA; however, these methylation changes do not directly control gene expression; and (3) OA would be more of a ‘dissolution problem’ rather than a ‘biomineralization problem’ for resilient species that maintain calcification rate with normal shell growth and mechanical properties.
The climatic debt is growing in the understorey of temperate forests: Stand characteristics matter
Authors: Richard Benoit , Dupouey Jean‐Luc , Corcket Emmanuel , Alard Didier , Archaux Frédéric , Aubert Michaël , Boulanger Vincent , Gillet François , Langlois Estelle , Macé Sébastien , Montpied Pierre , Beaufils Thérèse , Begeot Carole , Behr Patrick , Boissier Jean‐Michel , Camaret Sylvaine , Chevalier Richard , Decocq Guillaume , Dumas Yann , Eynard‐Machet Richard , Gégout Jean‐Claude , Huet Sandrine , Malécot Valéry , Margerie Pierre , Mouly Arnaud , Paul Thierry , Renaux Benoît , Ruffaldi Pascale , Spicher Fabien , Thirion Erwin , Ulrich Erwin , Nicolas Manuel , Lenoir Jonathan
Published: May 2021

Aim

Climate warming reshuffles biological assemblages towards less cold‐adapted but more warm‐adapted species, a process coined thermophilization. However, the velocity at which this process is happening generally lags behind the velocity of climate change, generating a climatic debt the temporal dynamics of which remain misunderstood. Relying on high‐resolution time series of vegetation data from a long‐term monitoring network of permanent forest plots, we aim at quantifying the temporal dynamics – up to a yearly resolution – of the climatic debt in the understorey of temperate forests before identifying the key determinants that modulate it.

Location

France.

Time period

1995–2017.

Taxa studied

Vascular plants.

Methods

We used the community temperature index (CTI) to produce a time series of understorey plant community thermophilization, which we subsequently compared to a time series of mean annual temperature changes over the same period and for the same sites. The direction and magnitude of the difference (i.e., the climatic debt) was finally analysed using linear mixed‐effect models to assess the relative contributions of abiotic and biotic determinants, including forest stand characteristics.

Results

We found a significant increase in CTI values over time (0.08–0.09 °C/decade), whereas the velocity of mean annual temperature changes was three times higher over the same period (0.22–0.28 °C/decade). Hence, the climatic debt increased over time and was greater in forest stands with higher basal area or older trees as well as under warmer macroclimate. By contrast, a greater frequency of anthropogenic disturbances decreased the climatic debt, while natural disturbances and herbivory had no impact.

Conclusions

Although often overlooked in understanding the climatic debt of forest biodiversity, changes in forest stand characteristics may modulate the climatic debt by locally modifying microclimatic conditions. Notably, the buffering effect of the upper canopy layer implies microclimate dynamics that may provide more time for understorey plant communities to locally adapt.
Touch and contact during COVID‐19: Insights from queer digital spaces
Authors: Cheded Mohammed , Skandalis Alexandros
Published: May 2021

The aim of this conceptual paper is to discuss the transformation of socialization processes due to the digitalization of entertainment and community formation during COVID‐19. More specifically, we focus on alternative modes of touch and contact within the context of queer digital entertainment spaces and question how the world is shaped and sensed in a (post‐) COVID‐19 era. Inspired by the work of Karen Barad on a quantum theory of queer intimacies, we highlight that the rise of hybridized experiences in‐between physical and digital spaces captures a series of spatiotemporal, material, and symbolic dimensions of touch and contact. We conclude by drawing implications for the future of organizations and work.
Comparison of single subject and population‐based pharmacokinetics for optimizing prophylaxis with simoctocog alfa in patients with haemophilia A
Authors: Astermark Jan , Olsson Anna , Chelle Pierre , Täckström Kinga , Walger Maria , Magnusson Maria , Iorio Alfonso
Published: May 2021

Introduction

The use of pharmacokinetic assessment for optimal prophylactic dosing of factor concentrates in haemophilia has gained increasing enthusiasm over the last decade. However, blood sampling on several occasions is burdensome and limited sampling using population‐based PK is appealing.

Aim

To compare the pharmacokinetics and dosing recommendations for prophylaxis using six‐point single subject versus population‐based method (WAPPS‐Hemo) for simoctocog alfa (Nuwiq®).

Methods

Twelve adult patients with severe haemophilia A received a factor VIII (FVIII) dose of ≈50 IU/kg, and the activity was measured pre‐infusion and at 30 min, 6, 9, 24 and 48 h post‐infusion. Half‐life (t1/2), weight‐normalized AUC and time to troughs of 5%, 3% and 1% were calculated. The correlation between the PK algorithms was assessed using intraclass correlations (ICC) and dosing estimations were provided.

Results

WAPPS‐Hemo yielded a slightly longer mean t1/2, but the overall correlation between the methods was good (ICC ≥0.79) The time to troughs of 5%, 3% and 1% showed ICCs ≥0.86. For all variables, the most converging limited time point was 6+48 h. Additional time points did not improve the correlation. Despite similar pharmacokinetics, the mean estimated dose for a specific trough level varied from 60% less to 20% more using the population‐based approach. The time to 1% and the corresponding dose was sensitive to the baseline assumption.

Conclusion

Our data support the use of population‐based PK for patients on simoctocog alfa prophylaxis but also indicates differences, stressing the importance of the sampling scheme and monitoring actual FVIII levels achieved.
Tolerability of four‐drug antiretroviral combination therapy in primary HIV‐1 infection
Authors: Burns JE , Stöhr W , Kinloch‐De Loes S , Fox J , Clarke A , Nelson M , Thornhill J , Babiker A , Frater J , Pett SL , Fidler S
Published: May 2021

Objectives

Rapid initiation of antiretroviral therapy (ART) is important for individuals with high baseline viral loads, such as in primary HIV‐1 infection (PHI). Four‐drug regimens are sometimes considered; however, data are lacking on tolerability. We aimed to evaluate the tolerability of four‐drug regimens used in the Research in Viral Eradication of HIV‐1 Reservoirs (RIVER) study.

Methods

At enrolment, ART‐naïve adult participants or those newly commenced on ART were initiated or intensified to four‐drug regimens within 4 weeks of PHI. Rapid start was defined as pre‐confirmation or ≤ 7 days of confirmed diagnosis. Primary and secondary outcomes were patient‐reported adherence measured by 7‐day recall and regimen switches between enrolment and randomization, respectively.

Results

Overall, 54 men were included: 72.2% were of white ethnicity, with a median age of 32 years old, 42.6% had a viral load of ≥ 100 000 HIV‐1 RNA copies/mL, and in 92.6% sex with men was the mode of acquisition of HIV‐1. Twenty (37%) started a four‐drug regimen and 34 (63%) were intensified. Rapid ART initiation occurred in 28%, 100% started in ≤ 4 weeks. By weeks 4, 12, and 24, 37.0%, 69.0%, and 94.0% were undetectable (viral load < 50 copies/mL), respectively. Adherence rates of 100% at weeks 4, 12, 22 and 24 were reported in 88.9%, 87.0%, 82.4% and 94.1% of participants, respectively. Five individuals switched to three drugs, four changed their regimen constituents, and two switched post‐randomization.

Conclusions

Overall, four‐drug regimens were well tolerated and had high levels of adherence. Whilst their benefit over three‐drug regimens is lacking, our findings should provide reassurance if a temporarily intensified regimen is clinically indicated to help facilitate treatment.
Formulation of Pickering emulsions for the development of surfactant‐free sunscreen creams
Authors: Bordes Claire , Bolzinger Marie‐Alexandrine , El Achak Myriam , Pirot Fabrice , Arquier Delphine , Agusti Géraldine , Chevalier Yves
Published: May 2021

Objective

Pickering emulsions are increasingly used in the pharmaceutical and cosmetic fields, especially for topical applications, since these systems require solid particles as emulsifiers instead of surfactants which are known to cause skin irritation. The solid inorganic nanoparticles (TiO2 and ZnO) used as UV filters in sunscreen formulations may also stabilize emulsion droplets, so that the utility of surfactants may be questioned. Surfactant‐free sunscreen emulsions solely stabilized by such nanoparticles (NPs) have been studied.

Methods

The ability of these NPs to stabilize o/w emulsions containing a ‘model’ oil phase, the C12‐C15 alkylbenzoate, has been assessed. ZnO and hydrophilic silica‐coated TiO2 NPs widely used in sunscreen products were used together with their mixtures. The emulsification efficiency, the control of droplet size and the stability of o/w Pickering emulsions solely stabilized by NPs were investigated. A ZnO/TiO2 NPs mixture characterized by a theoretical SPF of 45 was finally used as unique emulsifiers to develop a surfactant‐free sunscreen emulsion.

Results

Stable Pickering emulsions containing 10 up to 60 wt% of C12‐C15 alkyl benzoate were formulated with 2 wt% ZnO in the aqueous phase. The droplet size was controlled by the solid NPs content with respect to oil and the emulsification process. Hydrophilic TiO2 NPs did not allow the stabilization of emulsions. The substitution of TiO2 for ZnO up to 60–70 wt% in a 20/80 o/w emulsion was successfully performed. Finally, a ZnO/TiO2 NP mixture was tested as unique emulsifier system for the formulation of a sunscreen cream. Despite a lower viscosity, the obtained Pickering emulsion was stable and exhibited a photoprotective effect similar to the corresponding surfactant‐based sunscreen cream with an in vitro SPF of about 45.

Conclusion

Surfactant‐free Pickering emulsions can be stabilized by the UV‐filter nanoparticles for the manufacture of sunscreen products.
Effect of the local probiotics in the therapy of periodontitis A randomized prospective study
Authors: Minić Ivan , Pejčić Ana , Bradić‐Vasić Marija
Published: May 2021

Objectives

The use of local probiotics in the therapy of periodontitis is reflected in their ability to antagonize periodontopathogens and modulates the immune response of the host to the presence of pathogenic microorganisms. The aim of this study was to investigate the use of local probiotics in the treatment of periodontitis as an adjunctive therapy to scaling and root planning (SRP).

Methods

The study involved 80 patients diagnosed with periodontitis. All participants underwent SRP therapy. Semi‐solid probiotic was then locally applied to the periodontal pocket in randomly selected patients for the test group (40 of them). The other 40 patients were in the control group. Clinical parameters including periodontal pocket depth (PPD), bleeding on probing (BOP) and plaque index (PI) were measured at baseline, and at 7 and 30 days after treatment.

Results

Seven days after the applied therapy in the test and control group, there was a significant decrease in the values or BOP (p < .001), while the values of other parameters did not show a statistically significant difference (p < .05). One month after the therapy in both groups, there was a statistically significant difference in the values of all clinical parameters (p < .001).

Conclusions

Based on the results of this pilot study, it can be said that, during periodontal treatment, topical application of probiotics in combination with SRP increases the effectiveness of conventional non‐surgical therapy of periodontitis.
Identification and validation of novel biomarkers and therapeutics for pulpitis using connectivity mapping
Authors: Al‐Natour Banan , Rankin Robby , McKenna Robyn , McMillan Hayley , Zhang Shu‐Dong , About Imad , Khan Asma A. , Galicia Johnah C. , Lundy Fionnuala T. , El‐Karim Ikhlas A.
Published: May 2021

Aim

To create an irreversible pulpitis gene signature from microarray data of healthy and inflamed dental pulps, followed by a bioinformatics approach using connectivity mapping to identify therapeutic compounds that could potentially treat pulpitis.

Methodology

The Gene Expression Omnibus (GEO) database, an international public repository of genomics data sets, was searched for human microarray datasets assessing pulpitis. An irreversible pulpitis gene expression signature was generated by differential expression analysis. The statistically significant connectivity map (ssCMap) method was used to identify compounds with a highly correlating gene expression pattern. qPCR was used to validate novel pulpitis genes. An ex vivo pulpitis model was used to test the effects of the compounds identified, and the level of inflammatory cytokines was measured with qPCR, ELISA and multiplex array. Means were compared using the t‐test or ANOVA with the level of significance set at p ≤ .05.

Results

Pulpitis gene signatures were created using differential gene expression analysis at cutoff points p = .0001 and .000018. Top upregulated genes were selected as potential pulpitis biomarkers. Among these, IL8, IL6 and MMP9 were previously identified as pulpitis biomarkers. Novel upregulated genes, chemokine (C‐C motif) ligand 21 (CCL21), metallothionein 1H (MT1H) and aquaporin 9 (AQP9) were validated in the pulp tissue of teeth clinically diagnosed with irreversible pulpitis using qPCR. ssCMap analysis identified fluvastatin (Statin) and dequalinium chloride (Quaternary ammonium) as compounds with the strongest correlation to the gene signatures (p = .0001). Fluvastatin reduced IL8, IL6, CCL21, AQP9 (p < .001) and MMP9 (p < .05) in the ex vivo pulpitis model, while dequalinium chloride reduced AQP9 (p < .001) but had no significant effect on the other biomarkers.

Conclusions

AQP9, MT1H and CCL21 were identified and validated as novel biomarkers for pulpitis. Fluvastatin and dequalinium chloride identified by the ssCMap as potential therapeutics for pulpitis reduced selected pulpitis biomarkers in an ex vivo pulpitis model. In vivo testing of these licenced drugs is warranted.
The role of caveolin‐1 and endothelial nitric oxide synthase polymorphisms in susceptibility to prostate cancer
Authors: Aliyari Mahdieh , Elieh Ali Komi Daniel , Kiani Amir , Moradi Mahmoudreza , Tanhapour Maryam , Rahimi Zohreh , Mozafari Hadi , Mohammadi‐Noori Ehsan , Pourmotabbed Tayebeh , Vaisi‐Raygani Asad , Bahrehmand Fariborz
Published: May 2021

Caveolin‐1(cav‐1) is overexpressed in prostate cancer (PC) and is associated with progression of the disease. We investigated the effects of CAV1‐T29107A and endothelial nitric oxide synthase (eNOS) G894T polymorphisms on the serum levels of testosterone, NO and prostate‐specific antigen (PSA) in patients with PC. We genotyped cav‐1 and eNOS genes in 112 PC patients and 150 healthy controls by PCR‐RFLP. Serum levels ofandwere measured using spectrophotometry, and serum levels of testosterone and PSA were measured by ELISA. The frequencies of CAV1 genotypes A/T vs. A/A according to the dominant model AT + TT vs. AA genotype and T allele were significantly higher in PC patients in comparison with the control group and considerably increased the risk of disease by 2.19‐, 1.44‐ and 1.6‐fold, respectively. AT + TT genotypes were associated significantly with the increased risk of PC in those with smoking or diabetes by 3.08‐fold (P = .004). Individuals carrying concurrently the T allele of CAV1 A29107T and the T allele of eNOS G894T genes had a significantly increased risk of PC by 2.52‐fold (P = .009). We did not find any significant relationship between eNOS G894T genotypes and alleles with susceptibility to PC. Our results highlighted the significance of CAV1‐T29107A SNP but not (eNOS) G894T in the susceptibility to PC in our the population that we have studied.
A review of organizational research on acculturation from a nonwork–work spillover perspective: Content analysis and future research guidelines
Authors: Valenzuela Marcus A. , Nguyen Angela‐MinhTu D. , Taras Vasyl
Published: May 2021

Acculturation has played an important role in understanding the behaviours, intergroup relations and adjustment of cultural minorities in their mainstream national culture. Additionally, organizational research has shown that acculturation is associated with a range of work‐related variables. Prior reviews on acculturation have not approached the literature from this angle, which we termed a nonwork–work spillover perspective on acculturation. To fill this gap, we conducted a content analysis of quantitative empirical research to examine how acculturation from a nonwork–work spillover perspective has been studied in terms of its conceptualization and operationalization and what has been studied per its association with work‐related variables. This review is especially important given the complexity associated with the conceptualization and operationalization of acculturation, which may affect the validity of the interpretation of research results in this area. We also offer recommendations for addressing the extant research limitations and provide guidance for future research on acculturation in organizational settings.
Liraglutide pharmacokinetics and exposure‐response in adolescents with obesity
Authors: Carlsson Petri Kristin C. , Hale Paula M. , Hesse Dan , Rathor Naveen , Mastrandrea Lucy D.
Published: May 2021

Background

Obesity in adolescence presents a major public health challenge, often leading to obesity in adulthood with associated chronic disease.

Objectives

This study aimed to perform a population pharmacokinetic and exposure‐response analysis of liraglutide by meta‐analysis of data from trials conducted in children, adolescents and adults with obesity.

Methods

The population pharmacokinetic analysis investigated the effect of covariates body weight, age group (children, adolescents and adults) and sex on liraglutide exposure in adolescents compared with previous results in adults. The exposure‐response relationship of liraglutide for the change from baseline in body mass index standard deviation score (BMI SDS) was evaluated in adolescents and compared to that in adults.

Results

Body weight was the main covariate affecting liraglutide exposure, with lower exposures at higher body weights, whereas age group was of no importance and sex was of little importance. An exposure‐response relationship was demonstrated for liraglutide in both adolescents and adults as the decrease in BMI SDS from baseline increased in an exposure‐dependent manner with increasing liraglutide exposure.

Conclusions

The population pharmacokinetic analysis supported similar liraglutide exposures in adolescents and adults; body weight was the most important covariate affecting exposure. An exposure‐response relationship was established for liraglutide.
Adult social care managers speak out: Exploring leadership development
Authors: McCray Janet , Temple Paul Furness , McGregor Suzanna
Published: May 2021

As part of a 2‐year research project, 79 interviews were undertaken with adult social care (ASC) registered managers (RMs) in England. The study aimed to identify the factors that influence the leadership practice and priorities of RMs in their role in ASC at two points, before and after a leadership development programme (LDP). A critical framework of Bourdieu is used to explore and analyse how the RM's disposition plays out as they lead in the ASC sector. A narrative inquiry methodology was applied. Results found that a lack of funding and increasing regulation has added emotional stress to the RM leadership role and their motivation to lead. In order to cope, addressing the localised leadership development needs of the RMs was central and emotional wellness key. There is the potential for the ASC home to become a social arena for conflict between differing agency power relationships. By experiencing their preferred LDP, the RMs had gained insights into their position as a leader in ASC and how, by their own actions, they could both influence and shape it.
Prevalence and factors associated with advance health directives in frail older inpatients
Authors: O'Leary James J. , Reid Natasha , Hubbard Ruth E. , Peel Nancye M.
Published: May 2021

Background

Advance health directives (AHD) can be used to explore and document patient preferences for treatment and are therefore an important aspect of care planning.

Aims

To investigate the prevalence and factors associated with AHD among older inpatients.

Methods

This retrospective study included 6449 patients, aged ≥65 years referred for specialist geriatric consultation between 2007 and 2018 in Queensland, Australia. The interRAI‐Acute Care Comprehensive Geriatric Assessment tool was used to calculate a frailty index (FI), range 0–1, based on 52 possible deficits, and categorised into intervals of 0.1 for analysis. FI was also grouped according to previously reported cut points: fit (FI ≤0.25), moderately frail (FI >0.25–0.4), frail (FI >0.4–0.6) and severely frail (FI >0.6).

Results

An AHD was present in 1032 (16.0%) of 6449 patients. Those with an AHD were significantly frailer than those without an AHD (mean FI 0.52 vs 0.45; P < 0.001). Higher frailty (odds ratio (OR): 1.34 (1.27–1.40)), older age (OR: 1.04 (1.03–1.05)), living in an institution (OR: 1.33 (1.01–1.73)) and recent hospitalisation (OR: 1.42 (1.23–1.62)) were significantly associated with higher prevalence of AHD. Prevalence of AHD increased over time, from 7.6% (n = 66) in 2008 to 35.4% (n = 99) in 2017.

Conclusions

The presence of AHD is associated with sociodemographic factors, as well as higher frailty levels. Prevalence of AHD among inpatients has increased over the past decade but remains modest.