bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of the safe and efficacious dose of the selective progesterone receptor modulator vilaprisan for the treatment of patients with uterine fibroids by exposure–response modelling and simulation
Authors: Sutter Gabriele , Frei Matthias , Schultze‐Mosgau Marcus‐Hillert , Petersdorf Kathrin , Seitz Christian , Ploeger Bart A.
Published: July 2021

Aims

We report population pharmacokinetic (popPK) and exposure–response (E–R) analyses for efficacy (induced amenorrhoea [IA]) and safety (unbound oestradiol [E2] concentrations) of the selective progesterone receptor modulator vilaprisan. Results were used to inform the dose for the Phase 3 programme in patients with uterine fibroids.

Methods

A popPK model was developed using data from Phase 1 and 2 studies (including ASTEROID 1 and 2). The relationship between vilaprisan exposure (steady‐state AUC) and IA after oral administration of 0.5, 1, 2 or 4 mg/day over 3 months was analysed in ASTEROID 1 using logistic regression and qualified in ASTEROID 2 by comparing simulated and observed probability for IA after 2 mg/day. The exposure–E2 relationship was analysed visually.

Results

Vilaprisan clearance was 22.7% lower in obese vs non‐obese patients. The E–R relationship for IA in ASTEROID 1 was steep and consistent with ASTEROID 2, with a maximum probability (Pmax) of 59% (95% CI: 49–68%). The exposure at which 50% of Pmax is obtained was 36.9 μg*h/L (95% CI: 27.7–48.7 μg*h/L). Simulations showed that 36% of the patients will be below 90% of Pmax for IA after 1 mg/day compared to 2% after 2 mg/day. E2 levels tended to decrease with increasing exposure. While E2 levels remained largely within the physiologic follicular phase range, the clinical relevance of this decrease will be evaluated in long‐term studies.

Conclusions

A 2 mg/day dose was selected for Phase 3 as E–R analyses show this dose results in a close to maximum probability for IA, without any safety concerns noted.
Identification of different side effects between PARP inhibitors and their polypharmacological multi‐target rationale
Authors: Sandhu Daranjit , Antolin Albert A. , Cox Anthony R. , Jones Alan M.
Published: July 2021

Aims

The aim of this study was to determine the differences and potential mechanistic rationale for observed adverse drug reactions (ADRs) between four approved PARP inhibitors (PARPi).

Methods

The Medicines and Healthcare products Regulatory Authority (MHRA) Yellow Card drug analysis profiles and NHS secondary care medicines database enabled the identification of suspected ADRs associated with the PARPi in the UK from launch to 2020. The polypharmacology of the PARPi were data‐mined from several public data sources.

Results

The overall ADRs per 100 000 Rx identified across the four PARPi are statistically significant (χ2 test, P < .001). Rucaparib has the greatest relative suspected ADRs, which can be explained by its least clean kinome and physicochemical properties. The suspected gastrointestinal ADRs of rucaparib and niraparib can be ascribed to their kinase polypharmacology. Suspected blood and lymphatic system ADRs of PARPi can be linked to their high volume of distribution (Vd). The thrombocytopenia rate of niraparib > rucaparib > olaparib tracked with the Vd trend.

Hypertension is only associated with niraparib and could be explained by the therapeutically achievable inhibition of DYRK1A and/or transporters. Arrhythmia cases are potentially linked to the structural features of hERG ion‐channel inhibition found in rucaparib and niraparib. Enhanced psychiatric/nervous disorders associated with niraparib can be interpreted from the diverse neurotransporter off‐targets reported.

Conclusions

Despite their similar mode of action, the differential polypharmacology of PARP inhibitors influences their ADR profile.
Impact ofUGT1A1genotype on the efficacy and safety of irinotecan‐based chemotherapy in metastatic colorectal cancer
Authors: Iwasa Satoru , Muro Kei , Morita Satoshi , Park Young Suk , Nakamura Masato , Kotaka Masahito , Nishina Tomohiro , Matsuoka Hiroshi , Ahn Joong Bae , Lee Keun‐Wook , Hong Yong Sang , Han Sae Won , Cho Sang‐Hee , Zhang Dong‐Sheng , Fang Wei‐Jia , Bai Li , Yuan Xiang‐Lin , Yuan Ying , Yamada Yasuhide , Sakamoto Junichi , Kim Tae Won
Published: July 2021

The phase III AXEPT study showed the noninferiority of modified capecitabine plus irinotecan (mXELIRI) with or without bevacizumab relative to fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without bevacizumab as a second‐line treatment for metastatic colorectal cancer. We evaluated the associations between theUGT1A1genotype linked to adverse events—caused by irinotecan—and the efficacy and safety of mXELIRI and FOLFIRI. TheUGT1A1genotype was prospectively determined and patients were categorized into three groups according to WT (*1/*1), single heterozygous (SH; *28/*1 or *6/*1), and double heterozygous or homozygous (DHH; *28/*28, *6/*6, or *28/*6). Overall survival (OS), progression‐free survival, response rate, and safety were assessed. TheUGT1A1genotype was available in all 650 randomized patients (WT, 309 [47.5%]; SH, 291 [44.8%]; DHH, 50 [7.7%]). The median OS was 15.9, 17.7, and 10.6 months in the WT, SH, and DHH groups, respectively, with an adjusted hazard ratio (HR) of 1.53 (95% confidence interval [CI], 1.12‐2.09;P = .008) for DHH vs WT or SH. The median OS in the mXELIRI and FOLFIRI arms was 18.1 vs 14.3 months (HR 0.80; 95% CI, 0.62‐1.03) in the WT group, 16.3 vs 18.3 months (HR 1.04; 95% CI, 0.79‐1.36) in the SH group, and 13.0 vs 9.1 months (HR 0.71; 95% CI, 0.39‐1.31) in the DHH group, respectively. Modified capecitabine plus irinotecan with or without bevacizumab could be a standard second‐line chemotherapy in terms of efficacy and safety regardless of theUGT1A1genotype.
Meta‐analysis of time to extrusion of tympanostomy tubes by tympanic membrane quadrant
Authors: Ungar Omer J. , Baris Harel , Oron Yahav , Shilo Shahaf , Handzel Ophir , Warshavsky Anton , Horowitz Gilad , Abu Eta Rani , Muhanna Nidal , Carmel Neiderman Narin N.
Published: July 2021

Objectives

To investigate the published time to extrusion of tympanostomy tubes inserted in the various quadrants of the tympanic membrane.

Methods

Publications were selected by a search with ‘PubMed’, ‘Embase’ and ‘Web of Science’. A meta‐analysis of time to extrusion as a function of tympanic membrane quadrant intubation was performed.

Design, Setting, Participant‐Not relevant Main Outcome Measured

Extrusion rate of tympanostomy tubes inserted in the various quadrants of the tympanic membrane.

Results

Eleven studies describing 2232 tympanostomy tubes were enrolled into the quantitative meta‐analysis. The extrusion rate was evaluated at 3‐month intervals up to 24 months post‐intubation, and it did not differ significantly at any of the time points tested for the superior and inferior anterior quadrants. The cumulative extrusion rates were as follows: 11 and 9%, 32 and 23%, 59 and 36%, 80 and 67%, 87 and 70%, 88 and 82%, and 96 and 89% in the superior and anterior quadrants, respectively, at 3, 6, 9, 15, 18, 21 and 24 months post‐intubation, respectively.

Conclusion

Time to extrusion of tympanostomy tubes are similar for all 3 tympanic membrane quadrants. The anterior superior quadrant intubation has no superiority in terms of intubation time.
Children's long‐term retention is directly constrained by their working memory capacity limitations
Authors: Forsberg Alicia , Guitard Dominic , Adams Eryn J. , Pattanakul Duangporn , Cowan Nelson
Published: July 2021

We explored the causal role of individual and age‐related differences in working memory (WM) capacity in long‐term memory (LTM) retrieval. Our sample of 160 participants included 120 children (6–13‐years old) and 40 young adults (18–24 years). Participants performed a WM task with images of unique everyday items, presented at varying set sizes. Subsequently, we tested participants' LTM for items from the WM task. Using these measures, we estimated the ratio at which items successfully held in WM were recognized in LTM. While WM and LTM generally improved with age, the ability to transfer information from WM to LTM appeared consistent between age groups. Moreover, individual differences in WM capacity appeared to predict LTM encoding. Overall, these results suggested that LTM performance was constrained by experimental, individual, and age‐related WM limitations. We discuss the theoretical and practical implications of this WM‐to‐LTM bottleneck.
Relationship between cool and hot executive function in young children: A near‐infrared spectroscopy study
Authors: Moriguchi Yusuke
Published: July 2021

A theoretical distinction exists between the cool and hot aspects of executive function (EF). At the neural level, cool EF may be associated with activation in the lateral prefrontal cortex and the anterior cingulate cortex, whereas the orbitofrontal cortex may play a key role in hot EF. However, some recent studies have shown that young children show activity in the lateral prefrontal regions during hot EF tasks, suggesting that the distinction between hot and cool EF may not be as marked. Nevertheless, few neuroimaging studies have directly examined the relationship between cool and hot EF. In this study, preschool children (N = 46, mean age = 66.1 months) were given both cool (Dimensional Change Card Sort (DCCS) and Stroop‐like tasks) and hot (delay of gratification) EF tasks, and neural activation during these tasks was measured using functional near‐infrared spectroscopy (fNIRS). Correlational analyses and analysis of variance (ANOVA) were conducted to assess the relationship between cool and hot EF. At the behavioral level, a moderate correlation was found between DCCS and Stroop‐like tasks, but no correlation emerged between cool and hot EF tasks. At the neural level, prefrontal activations during the cool EF tasks did not correlate with those during the hot EF task. Further, children showed stronger prefrontal activations during the DCCS tasks compared to the delay of gratification tasks. The results suggest that the neural basis of hot and cool EF may differ during early childhood.
What people with diabetes in Denmark worry about during the COVID‐19 pandemic: A longitudinal study of the first 3 months of the COVID‐19 pandemic
Authors: Joensen Lene Eide , Steenberg Josephine Lyngh , Madsen Kristoffer Panduro , Willaing Ingrid
Published: July 2021

To investigate and characterise general and diabetes‐specific worries related to COVID‐19 among people with diabetes in Denmark during the first 3 months of the pandemic.

In a longitudinal study from March to June 2020, six online questionnaires (Q1–Q6) were distributed to 2430 adult members of two diabetes panels. Worries related to COVID‐19 were measured with closed‐ and open‐ended items. Data from closed‐ended items were analysed descriptively. Open‐ended responses were analysed with systematic text condensation. Using chi‐squared tests, changes in proportions of worries over time were analysed, and differences in diabetes‐specific worries by gender and diabetes diagnosis were explored.

At Q1, 1366 individuals returned a response (Q2: 1082, Q3: 992, Q4: 977, Q5: 901, Q6: 816). In the beginning of the pandemic, 2 weeks after the first lockdown in Denmark, the most frequently reported general worries related to someone close becoming seriously ill, changes in daily life such as limitations on social interactions and uncertainty about the duration of those changes. The most frequently reported diabetes‐specific worries were about severity of illness with COVID‐19 due to diabetes, being identified as a member of a group at risk for COVID‐19 and being unable to manage diabetes if ill with COVID‐19. All concerns decreased over 3 months, as the society gradually reopened, except for persistent worries about being able to manage diabetes if ill with COVID‐19. More women and people with type 1 diabetes reported worries, compared with men and people with type 2 diabetes.

Our study highlights the diversity of worries related to the COVID‐19 pandemic among people with diabetes and changing patterns of worry over time and across subgroups as the society reopened in Denmark. These insights can be helpful when providing support for people with diabetes during health crises.
Unraveling the etiology of myelin disorders: the P2 case in Charcot–Marie–Tooth disease
Authors: Pusterla Julio , Montich Guillermo G. , Oliveira Rafael G.
Published: July 2021

There are several examples of single mutations that lead to a well‐defined disease through a well‐known mechanism. In other cases, a collection of mutations of the same protein produces a pathology with different degrees of severity. The accompanying work by Uusitalo et al. studies several mutants of the fatty acid binding protein P2 of the peripheral nervous system myelin. They conserve the native tertiary structure but a remarkable difference in the capacity to interact with lipids. This could be a clue to unravel the complex way in which these mutations affect myelin structure and function in a variant of Charcot–Marie–Tooth disease.

Comment on: https://doi.org/10.1111/febs.16079
“Story time is my duty”: Expatriate academic fathers' experiences of balancing their work and home lives
Authors: Dickson Martina , Dickson James
Published: July 2021

An academic's life is acknowledged to be the one with constant pressure to publish, as well as fulfilling teaching and other tasks. Much has been written about the academic mother's experience, where professional gain is often reported to be at personal expense. Academic fathers' experiences are less explored, and usually situated within their own home countries. This article presents a qualitative narrative research of male faculty parents working in the United Arab Emirates in the Arabian Gulf. The ways in which the academic fathers “perform” fatherhood, strive to find balance in their lives, and create space for the necessary work of academic research are explored. The findings indicate that where work pressures are experienced, their home support systems (namely spousal support, but also paid domestic help) compensated for this in a way which does not appear to incur self‐sacrifice or career impact. The academic fathers generally reported feeling supported and validated by their organizations and host country.
Gelatin extraction from fish waste and potential applications in food sector
Authors: Usman Muhammad , Sahar Amna , Inam‐Ur‐Raheem Muhammad , Rahman Ubaid ur , Sameen Aysha , Aadil Rana Muhammad
Published: July 2021

Fish solid wastes include different by‐products such as bones, scales and hides that are high in collagen content and account for up to 75% of the total body weight. These wastes can be utilised for the extraction of different products such as gelatin that can be used in different food and pharmaceutical industries. Fish gelatin can be used as a replacement for mammalian gelatin due to its nutritional profile as it contains all the amino acids: essential and non‐essential. Fish gelatin cannot only be used as a replacement for bovine and porcine gelatin but it also increases the utilisation of fish waste and reduces pollution. This review summarises the potential utilisation of different fish waste byproducts, extraction techniques and its application in different food products as an alternative to commercially available porcine and bovine gelatin.
Cities’ migration policies in a country with a deficit of migration policy. The case of Poland
Authors: Ślęzak Ewa , Bielewska Agnieszka
Published: July 2021

Poland is currently characterized by no migration policy in a form of an officially approved document as well as by the dominating anti‐immigrant rhetoric expressed by the ruling party leaders. The aim of this paper was to show how Polish cities deal with the unprecedented migration influx in the context of lack of officially approved national level strategy. As the cities’ authorities attitudes vary from accepting migration as economically beneficial to treating migrants as part of the urban population, the unclear state policy is recognized by some as a silent permission of the state to incorporate of migrants. Officially it could not be seen a part of state policy as it is contradicting the anti‐immigration rhetoric. Our paper shows also how the cities’ policies clash with the state approach and policies, in particular at the local level, where the state administration may jeopardize the welcoming messages sent by city authorities towards migrants.
Two heuristics for the label printing problem
Authors: Alonso‐Pecina Federico , Arellano‐Verdejo Javier , Diego‐Celis Rocio
Published: July 2021

The label printing problem (LPP) arises in the printing industry, where we have a set of labels that require printing. Each one has different demands and must be printed using a single template. The number of labels we can allocate in a template is a fixed one, and the number of templates varies in a small range of different sizes. The goal of the LPP is to design templates to meet the demands for the labels while minimizing the percentage of material wasted. In each grid, the need for each printed cover must be met to facilitate label management. To deal with LPP, we used two known metaheuristics: a threshold accepting and a tabu search. These heuristics, with the aid of a Hill climbing double neighborhood, improved the results significantly.
Short‐term heat stress during flowering results in a decline in Canola seed productivity
Authors: Lohani Neeta , Singh Mohan B. , Bhalla Prem L.
Published: July 2021

Oilseed rape (Brassica napus) or Canola is an important oilseed crop produced and consumed globally. The predicted increase in the frequency of high‐temperature events associated with climate change poses a threat to Canola productivity. In the present work, we report the impact of short‐term heat stress on the reproductive fitness and yield components of Canola. Short heat stress episodes, especially above 36°C, resulted in diminished reproductive fitness due to reduced pollen viability and germinability. Heat stress exposure led to asynchronous male and female development and suppressed pollen development in developing buds. As the temperature increased above 32°C, the seed production decreased significantly. Temperatures beyond 38°C resulted in >50% reduction in total seed production and seed weight. Short‐term heat stress also reduced yield components, seed vigour and post‐harvest seed characteristics. Biochemical investigations of the seeds harvested from heat‐stressed (40°C for 12 hr) plants showed decreased oil content along with a variable fatty acid composition. The omega‐6/omega‐3 ratios increased in response to heat stress indicated a possible decline in oil nutritional quality. Understanding the impact of short heat stress episodes can provide efficient heat tolerance screening tools and pave the way for developing heat stress‐tolerant B. napus varieties.
Effects of 405 nm light‐emitting diode treatment on microbial community on fresh‐cut pakchoi and antimicrobial action against Pseudomonas reinekei and Pseudomonas palleroniana
Authors: Zhang Yuchen , Xie Jing
Published: July 2021

Pakchoi (Brassica rapa L. Chinensis) is an important cruciferous vegetable crop in East and Southeast Asia. This research aimed to investigate the change of microbial community and antibacterial effect of 405 nm light‐emitting diode (LED405 nm) illumination (15 μ mol/(m2 · s)) against spoilage bacteria on the surface of agar media and fresh‐cut pakchoi. High‐throughput community sequencing was used to quantify bacterial abundance and 16S rRNA was used to analyze the bacterial community composition on fresh‐cut pakchoi treated with or without LED405 nm storage at 4°C. And alkaline phosphatase (AKP) activity and metabolic inhibition assays were selected to measure the mechanism of bacterial inhibition. The results showed that Pseudomonas spp. were able to multiply and cause spoilage of fresh‐cut pakchoi at 4°C. Nevertheless, the majority of Pseudomonas spp. isolated from spoilage pakchoi were Pseudomonas reinekei and Pseudomonas palleroniana which were considered as representative specific spoilage microorganisms in pakchoi. Furthermore, 405 nm light treatment retarded sensory deterioration, inhibited microbial growth. AKP activity and metabolic inhibition assays confirmed the inhibitory effect of light treatment. In brief, 405 nm LED illumination has potential as a preservative to maintain quality, extend the shelf life for 6 days of fresh‐cut pakchoi and abled to control P. reinekei and P. palleroniana growth on fresh‐cut pakchoi at 4°C.
Allopregnanolone: The missing link to explain the effects of stress on tic exacerbation?
Authors: Bortolato Marco , Coffey Barbara J. , Gabbay Vilma , Scheggi Simona
Published: July 2021

The neurosteroid allopregnanolone (3α‐hydroxy‐5α‐pregnan‐20‐one; AP) elicits pleiotropic effects in the central nervous system, ranging from neuroprotective and anti‐inflammatory functions to the regulation of mood and emotional responses. Several lines of research show that the brain rapidly produces AP in response to acute stress to reduce the allostatic load and enhance coping. These effects not only are likely mediated by GABAA receptor activation but also result from the contributions of other mechanisms, such as the stimulation of membrane progesterone receptors. In keeping with this evidence, AP has been shown to exert rapid, potent antidepressant properties and has been recently approved for the therapy of moderate‐to‐severe postpartum depression. In addition to depression, emerging evidence points to the potential of AP as a therapy for other neuropsychiatric disorders, including anxiety, seizures, post‐traumatic stress disorder and cognitive problems. Although this evidence has spurred interest in further therapeutic applications of AP, some investigations suggest that this neurosteroid may also be associated with adverse events in specific disorders. For example, our group has recently documented that AP increases tic‐like manifestations in several animal models of tic disorders; furthermore, our results indicate that inhibiting AP synthesis and signalling reduces the exacerbation of tic severity associated with acute stress. Although the specific mechanisms of these effects remain partially elusive, our findings point to the possibility that the GABAergic activation by AP may also lead to disinhibitory effects, which could interfere with the ability of patients to suppress their tics. Future studies will be necessary to verify whether these mechanisms may apply to other externalising manifestations, such as impulse‐control problems and manic symptoms.
Aroma analyses of fermented soybean paste (doenjang) using descriptive sensory analysis and μ‐chamber/thermal extractor combined with thermal desorber–gas chromatography–mass spectrometry
Authors: Jang Hae Won , Yu Ja Myung , Kim Mina K.
Published: July 2021

The objective of this study was to conduct comprehensive aroma analyses of fermented soybean paste (doenjang) using descriptive sensory analysis and μ‐CTE–TD–GC–MS. Four doenjang samples were analyzed for its aroma using μ‐CTE–TD–GC–MS. Descriptive analysis was carried out with a highly trained panel (n = 6). A total of 38 volatile compounds were identified and significant differences in concentrations were noted especially between traditionally manufactured doenjang (S1) and commercially manufactured doenjang (S2–S4) samples. Authentically produced traditional doenjang samples (S1) characterized with meju, fish sauce, and roasted bean aromatics and these are previously reported as typical aromatics associated with traditional doenjang. Higher concentrations of Streker aldehydes and 3‐hydroxy‐2‐butanone, 2‐hydroxy‐3‐pentanone, and butanoic acid were exclusively found in S1. Commercially manufactured doenjang samples were characterized with high alcohol and fruity aromatics and volatile compounds in alcohol and ester compounds were found in higher concentration than S1. Addition of different flavor enhancer also influenced the aroma characteristics of commercially manufactured doenjang, which seems irrelevant to soybean fermentation.

Practical applications

This study provides the most abundant list of sensory descriptors for traditional doenjang, which can be used as a baseline for doenjang aroma wheel. In addition, this study confirms the use of μ‐CTE–TD–GC–MS for volatile aroma analysis to provide same or superior extraction efficiency for volatile aroma analysis. Overall, this study confirms the aroma differences between “traditionally made” doenjang and “commercially made” doenjang. Interestingly commercial doenjang advertised as “traditionally made doenjang” had different aroma characteristics than authentic, traditionally made doenjang. Finding from current study can assist the doenjang industry to strategically designing the traditional doenjang aroma development targeting for different consumer segments.
Periodontitis exacerbates the renal degenerative effects of obesity in rats
Authors: Kurt‐Bayrakdar Sevda , Kose Oğuz , Altin Ahmet , Akyildiz Kerimali , Mercantepe Tolga , Bostan Semih Alperen , Kose Taha Emre , Tumkaya Levent , Yilmaz Adnan
Published: July 2021

Background/objectives

Obesity and periodontitis are systemic subclinical inflammatory diseases with established negative renal effects. The aim of this animal study was to thoroughly investigate the possible effects of these two diseases on renal structure and function.

Methods

Thirty‐two male Sprague Dawley rats were divided into four groups: control (C), obesity (Ob), experimental periodontitis (Ep), and Ob + Ep. The first 16 weeks of the experiment were aimed for the induction of obesity and the last 5 weeks for the induction of periodontitis. Throughout the experimental period, the C and Ep groups were fed standard rat chow, while the Ob groups (Ob and Ob + Ep) were fed high‐fat rat chow. Right after the establishment of obesity, periodontal tissue destruction was achieved by placing 3.0 silk sutures in sub‐paramarginal position around the cervices of mandibular right‐left first molar teeth and preserving them for 5 weeks. On the last day of the 22nd week, following blood collection, all rats were euthanized, and kidneys and mandibles were collected. Alveolar bone loss was measured on microcomputed tomographic slices. Histopathological evaluations (light microscopy, semi‐quantitative analysis of renal corpuscle area, and immunohistochemical analysis of caspase‐3 activity) were done on right kidneys and biochemical evaluations (malonyl‐aldehyde [MDA], glutathione [GSH], total oxidant status [TOS], total antioxidant status [TAS], oxidative stress [OSI], tumor necrosis factor‐α [TNF‐α], interleukin‐1β [IL‐1β], matrix metalloproteinase [MMP]‐8, MMP‐9, and cathepsin D [CtD] levels) were done on left kidneys. Renal functional status was evaluated with levels of serum creatinine, urea, and cystatin C.

Results

Periodontal bone loss was significantly higher in the Ep and Ob + Ep groups, compared with the C and Ob groups (p < .05). All parameters except TAS and GSH were highest in the Ob + Ep group, and the differences were statistically significant compared with the control group (p < .05). Although the mean TAS and GSH levels were lower in the Ob + Ep group than the other groups, the differences were not statistically significant (p > .05). While the atypical glomeruli score was significantly higher in the Ob + Ep group than in all other groups (p < .05), the acute tubular necrosis and histopathological scores were significantly different only compared with the control group (p < .05).

Conclusion

This experimental study showed that the negative effects of the co‐existence of periodontitis and obesity on inflammatory stress and apoptotic changes in the kidneys together with the functional parameters were significantly more severe, compared with the presence of one of these diseases alone. TNF‐α could have a central role in the periodontitis and obesity‐related structural and functional renal changes.
Zonation in NASH – A key paradigm for understanding pathophysiology and clinical outcomes
Authors: Steinman Jonathan B. , Salomao Marcela A. , Pajvani Utpal B.
Published: July 2021

Non‐alcoholic fatty liver disease (NAFLD) exists as a spectrum ranging from simple steatosis to histologically defined hepatocyte injury and inflammatory changes that define steatohepatitis (NASH), and increase risk for fibrosis. Although zonal differences in NASH have not been systematically studied, periportal involvement has been associated with worse metabolic outcomes and more hepatic fibrosis as compared to pericentral disease. These data suggest that hepatic zonation of disease may influence the diversity of clinical presentations. Similarly, several randomized clinical trials suggest a differential response based on zonation of disease, with preferential effects on periportal (cysteamine) or pericentral disease (obeticholic acid, pioglitazone). Intriguingly, morphogenic pathways known to affect zonal development and maintenance – WNT/β‐Catenin, Hedgehog, HIPPO/Yap/TAZ and Notch – have been implicated in NASH pathogenesis, and nuclear hormone receptors downstream of potential NASH therapeutics show zonal preferences. In this review, we summarize these data and propose that patient‐specific activation of these pathways may explain the variability in clinical presentation, and the zone‐specific response observed in clinical trials.
The price tag of a potential cure for chronic hepatitis B infection: A cost threshold analysis for USA, China and Australia
Authors: Toy Mehlika , Hutton David , McCulloch Karen , Romero Nicole , Revill Peter A. , Penicaud M‐Capucine , So Samuel , Cowie Benjamin C.
Published: July 2021

Background & Aims

We aim to capture the economic impact of a potential cure for chronic hepatitis B infection (CHB) in three countries (USA, China and Australia) with different health systems and epidemics to estimate the threshold drug prices below which a CHB cure would be cost‐saving and/or highly cost‐effective.

Methods

We simulated patients’ hepatitis B progression, under three scenarios: current long‐term suppressive antiviral therapy, functional cure defined as sustained undetectable HBsAg and HBV DNA, and partial cure defined as sustained undetectable HBV DNA only after a finite, 48‐week treatment.

Results

Compared with current long‐term antiviral therapy, a 30% effective functional cure among patients with and without cirrhosis in the USA, China and Australia would yield 17.50, 17.32 and 20.42 QALYs per patient, and 20.61, 20.42 and 20.62 QALYs per patient respectively. In financial terms, for CHB patients with and without cirrhosis, this would be cost‐saving at a one‐time treatment cost under US$11 944 and US$6694, respectively, in the USA, US$1744 and US$1001 in China, and US$12 063 and US$10 983 in Australia.

Conclusion

We show that in purely economic terms, a CHB cure will be highly cost‐effective even if effective in only 30% of treated patients. The threshold price for cure is largely determined by the current antiviral drug costs, since it will replace a daily antiviral pill that is inexpensive and effective, although not curative. The likely need for combination therapies to achieve cure will also present cost challenges. While cost‐effectiveness is important, it cannot be the only consideration, as cure will provide many benefits in addition to reduced liver disease and HCC, including eliminating the need for a long‐term daily pill and reducing stigma often associated with chronic viral infection.
On buybacks, dilutions, dividends, and the pricing of stock‐based claims
Authors: Backwell Alex , McWalter Thomas A. , Ritchken Peter H.
Published: July 2021

We develop a structural model of the firm that accounts for dilutions, resulting from interest payment shortfalls, and allows cash surpluses to be distributed under a payout policy that permits a combination of dividends and buybacks. Since the model tracks the number of outstanding shares, it can distinguish between claims dependent on the price of a share versus claims that depend on total equity. With a further extension of the model to incorporate employee stock grants, we demonstrate how the prices of traded stock options and employee grants are affected by payout policy. The impact of both dilutions and buybacks on traded option prices and employee grants is shown to be material. This magnitude is further illustrated through a case study involving five technology firms.
Mythology, history, and reality: Mythorealism in Yan Lianke’sThe Explosion Chronicles
Authors: Liu Yang , Wang Shouren
Published: July 2021

“Miraculous” is a word often used to describe the rapid development of urbanization that have taken place in China in the past 30 years. Yan Lianke’s fictional historiography,The Explosion Chronicles, probes into the stories behind the economic miracles with an eye especially for the aspects that are against the common logic of reality. It is an experiment contrived according to his own theory of mythorealism—a literary attempt to grasp reality that is not in existence, out of sight, and concealed by other superficial realities. This article argues that by constantly challenging the authority of truth, Yan Lianke showcases in this novel a new way of grasping reality that is different from the magical realism’s approach.The Explosion Chroniclescan be read as a development mythology that is framed by important mythological themes from ancient Chinese mythological discourses, not only blurring the distinctions between the rational and the mythical, but also adopting a whole different logic of progress. By assuming the narrative voice of a novelist commissioned to write a historical account for a fast‐developing metropolis, Yan Lianke undertakes the task of revealing the constant historical truth underlying the changing realities, embodying an understanding of the historical progress similar to Walter Benjamin’s visualization of an angel facing the accumulating wreckages of the past.
The Political Psychology of COVID‐19
Authors: Muldoon Orla T. , Liu James H. , McHugh Cillian
Published: July 2021

The COVID‐19 pandemic has given rise to unprecedented and extraordinary conditions. It represents a profound threat to health and political and economic stability globally. It is the pressing issue of the current historical moment and is likely to have far‐reaching social and political implications over the next decade. Political psychology can inform our preparedness for the next phase of the pandemic as well as our planning for a post COVID‐19 world. We hope that this special issue will play its part in helping us to think how we manage and live with COVID‐19 over the coming decade. In this editorial, we review the key themes arising from the contributions to our special issue and, alongside existing knowledge highlight the relevance of political psychology to finding solutions during this time of crisis. The contributions to this special issue and the pandemic raise many classic topics of central interest to political psychology: leadership, solidarity and division, nationalism, equality, racism, and international and intergroup relations. In our editorial, we offer an analysis that highlights three key themes. First, the importance of sociopolitical factors in shaping behavior during this pandemic. Second, the relevance of political leadership and rhetoric to collective efforts to tackle SARS‐COV‐2. And third, how sociopolitical cohesion and division has become increasingly relevant during this time of threat and crisis.
A review of knowledge on the mechanisms of action of the rare sugard‐tagatose against phytopathogenic oomycetes
Authors: Chahed Abdessalem , Nesler Andrea , Aziz Aziz , Barka Essaid A. , Pertot Ilaria , Perazzolli Michele
Published: July 2021

d‐tagatose is a rare monosaccharide, naturally present at low concentrations in some fruits and dairy products.d‐tagatose is "generally recognized as safe" and is used as a low‐calorie sweetener in the food industry.It is able to inhibit the growth of numerous microorganisms, such as phytopathogenic oomycetes responsible for important crop diseases. Thanks to the negligible effects on human health and the environment,d‐tagatose has been proposed as a sustainable product for crop protection. This review describes the current knowledge on modes of action ofd‐tagatose against phytopathogenic oomycetes and its potential uses in agriculture.d‐tagatose can negatively affect the growth of phytopathogenic oomycetes by inhibiting key enzymes of sugar metabolism, such as β‐glucosidase inPhytophthora infestans, and fructokinase and phosphomannose isomerase inHyaloperonospora arabidopsidis. Moreover,d‐tagatose affects sugar content, causes severe mitochondrial alterations, and inhibits respiration processes with the accumulation of reactive oxygen species inP.infestans, but not inP.cinnamomi. Differential effects ofd‐tagatose are associated with a global gene downregulation inP.infestansand with an efficient transcriptional reprogramming of multiple metabolic processes inP.cinnamomi.d‐tagatose displays possible species‐specific effects inPhytophthoraspp. and nutritional properties on some plant‐associated microorganisms. However, inhibitory effects are reversible andP.infestansgrowth can be restored in the absence ofd‐tagatose. Further functional studies are discussed in this review, in order to promote the use ofd‐tagatose for sustainable crop protection.
Public participation in decision‐making on conservation translocations: the importance and limitations of a legislative framework
Authors: Klein Lisette , Arts Koen
Published: July 2021

Conservation translocations are a frequently used management tool applied by nature conservationists. Many conservation translocations have a low success rate, which is caused by various biological and societal factors. While conservation translocations are often set in human‐dominated landscapes, they tend to be poorly embedded in social‐ecological systems. Indeed, the primacy of biological aspects in translocation processes seems to undercut attention for societal dimensions. A key societal dimension is public participation. In this article, we identified and analyzed processes that affect the implementation of public participation. In addition, we considered whether, and under which circumstances, a legislative framework enables meaningful public participation. We used a Policy Arrangement Approach to grasp the processes at play. Sixteen semi‐structured interviews were conducted with key‐actors involved in the design and planning of conservation translocations in Scotland. Interviewees argued that inclusive decision‐making was either unintentionally or deliberately neglected. Underlying causes related to regularly witnessed barriers such as traditional expert‐driven approaches, entrenched power relations, and uncertainties on how to deliver open and inclusive public participation practices. Moreover, there was a mismatch between conservationists' expectations on how public participation should be implemented and recognized fundamentals of public participation, e.g. transparency and dialogue. The results demonstrate that while a legislative framework raises awareness and provides guidance, it is unable to take away current barriers. Due to the uncertainties around democratic decision‐making, it is unrealistic to expect that a mere legislative framework alone would solve current challenges. Yet, conversely the absence of one may increase current challenges.
Process effects of multistakeholder institutions: Theory and evidence from the Open Government Partnership
Authors: Berliner Daniel , Ingrams Alex , Piotrowski Suzanne J.
Published: July 2021

How does membership in transnational multistakeholder institutions shape states' domestic governance? We complement traditional compliance‐based approaches by developing a process model, focusing on the independent effects of processes associated with institutional membership, but separate from commitments and compliance themselves. These effects can be driven by iterative and participatory institutional features, which are increasingly prevalent in global governance. We apply this model to the Open Government Partnership (OGP), a transnational multistakeholder initiative with nearly 80 member countries, featuring highly flexible commitments and weak enforcement. Although commitments and compliance have generally been limited, a compliance‐focused approach alone cannot account for myriad other consequences globally and domestically, driven by the iterative and participatory features associated with membership. We demonstrate these at work in a case study of Mexico's OGP membership, which contributed to the spread of new norms and policy models, new political resources and opportunities for reformers, and new linkages and coalitions.
Du Châtelet on Sufficient Reason and Empirical Explanation
Authors: Wells Aaron
Published: July 2021

For Émilie Du Châtelet, I argue, a central role of the principle of sufficient reason is to discriminate between better and worse explanations. Her principle of sufficient reason does not play this role for just any conceivable intellect: it specifically enables understanding for minds like ours. She develops this idea in terms of two criteria for the success of our explanations: “understanding how” and “understanding why.” These criteria can respectively be connected to the determinateness and contrastivity of explanations. The crucial role Du Châtelet’s principle of sufficient reason plays in identifying good explanations is often overlooked in the literature, or else run together with questions about the justification and likelihood of explanations. An auxiliary goal of the article is to situate Du Châtelet’s principle of sufficient reason with respect to some of the general epistemological and metaphysical commitments of her Institutions de Physique, clarifying how it fits into the broader project of that work.
Fatal recurrent disseminated Lomentospora prolificans infection during autologous hematopoietic stem cell transplantation: A case report and review, and discussion on the importance of prolonged neutropenia
Authors: Gow‐Lee Vanessa J. , Moyers Justin T. , Rogstad Daniel K.
Published: July 2021

Infections with Scedosporium and Lomentospora species, in particular Lomentospora (previously Scedosporium) prolificans, are nearly universally fatal and rapidly‐progressive in the transplant population. We report a case of a patient with diffuse large B‐cell lymphoma undergoing myelosuppressive chemotherapy who developed disseminated L. prolificans infection which afterward persisted in his knee joint. The infection was treated with early empiric triple antifungal therapy tailored to synergy studies, growth factors to quickly resolve neutropenia, and aggressive debridement (where possible) of infection sites, including amputation. He achieved an 11‐month remission until undergoing autologous hematopoietic stem cell transplantation with deep myelosuppression, wherein recrudescent L. prolificans infection occurred, causing death. We highlight the importance of early treatment, synergy studies, and especially recovery of neutropenia in treating this devastating condition.
Measurements of Static and Dynamic Load Performance of a 102 MM Carbon-Graphite Porous Surface Tilting-Pad Gas Journal Bearing
Authors: San Andrés Luis , Yang Jing , McGowan Ryan
Published: July 2021

Aerostatic journal bearings with porous tilting pads enable shaft support with minute drag power losses. To date archival information on the static and dynamic load performance of this bearing type is scant. Thus, the paper presents measurements conducted with an air lubricated bearing with diameter d = 102 mm and comprising four tilting pads made of porous carbon-graphite, each with length L = 76 mm. Two nested Belleville washers resting on spherical pivots support each pad. At ambient temperature of ∼ 21 °C, as the air supply pressure into the bearing pads increases, so does the bearing aerostatic specific load (F/(L·d)) that reaches 58% of the pressure difference, supply minus ambient. With an air supply pressure of 7.8 bar(a), the test bearing static stiffness KS = 13.1 MN/m, is independent of both shaft speed and static load. KS is just 63% of the washers' stiffness KP = 20.6 MN/m (during loading). While operating with shaft speeds equal to 6 krpm and 9 krpm (150 Hz) and under specific loads to 115 kPa and 101 kPa, respectively, dynamic load experiments with excitation frequencies up to 342 Hz show the test bearing supplied with air at 7.8 bar(a) has frequency independent stiffness (K) and damping (C) coefficients. For rotor speeds equaling 0, 6 and 9 krpm, the bearing direct stiffnesses KXX ∼ KYY range from 13.6 MN/m to 32.7 MN/m as the specific load increases from 0 kPa to 115 kPa. The direct damping coefficients CXX ∼ CYY are as large as 5.8 kN·s/m, though having a large experimental uncertainty. Bearing cross-coupled force coefficients are insignificant. The test porous gas bearing reached its intended load capacity, demonstrated a dynamically stable operation and produced force coefficients mainly affected by the pads' pivot supports and the magnitude of air supply pressurization.
Applied science facilitates the large-scale expansion of protected areas in an Amazonian hot spot
Authors: Pitman Nigel C.A. , Vriesendorp Corine F. , Alvira Reyes Diana , Moskovits Debra K. , Kotlinski Nicholas , Smith Richard C. , Thompson Michelle E. , Wali Alaka , Benavides Matarazzo Margarita , del Campo Álvaro , Rivera González Dani E. , Rivera Chávez Lelis , Rosenthal Amy D. , Álvarez Alonso José , Díaz Ñaupari María Elena , de Souza Lesley S. , Ferreyra Vela Freddy R. , Gonzales Tanchiva Cristian Ney , Jarrett Christopher C. , Lemos Ana A. , Sáenz Rodríguez Ana Rosa , Stotz Douglas F. , Suwa Tomomi , Pariona Fonseca Mario , Ravikumar Ashwin , Torres Tuesta Teofilo , Bravo Adriana , Catenazzi Alessandro , Díaz Alván Juan , Gagliardi-Urrutia Giussepe , García-Villacorta Roosevelt , Hidalgo Max H. , Mori Vargas Tony , Mueses-Cisneros Jonh J. , Núñez-Iturri Gabriela , Pequeño Tatiana , Ríos Paredes Marcos A. , Rodríguez Lily O. , Stallard Robert F. , Torres Montenegro Luis A. , Venegas Pablo J. , von May Rudolf , Barbagelata Ramírez Nélida , Maldonado Ocampo Javier A. , Mesones Acuy Italo
Published: July 2021

Since 2000, collaborative and multidisciplinary field inventories have helped quadruple park coverage in Peru’s richest region.
North Atlantic Oscillation in winter is largely insensitive to autumn Barents-Kara sea ice variability
Authors: Siew Peter Yu Feng , Li Camille , Ting Mingfang , Sobolowski Stefan P. , Wu Yutian , Chen Xiaodan
Published: July 2021

Accounting for internal variability reveals insights into mechanisms underlying an Arctic–mid-latitude teleconnection riddle.
Single-cell analyses unravel cell type–specific responses to a vitamin D analog in prostatic precancerous lesions
Authors: Abu el Maaty Mohamed A. , Grelet Elise , Keime Céline , Rerra Anna-Isavella , Gantzer Justine , Emprou Camille , Terzic Julie , Lutzing Régis , Bornert Jean-Marc , Laverny Gilles , Metzger Daniel
Published: July 2021

Anti- and protumoral effects of a vitamin D analog revealed at single-cell resolution.
Bird neurocranial and body mass evolution across the end-Cretaceous mass extinction: The avian brain shape left other dinosaurs behind
Authors: Torres Christopher R. , Norell Mark A. , Clarke Julia A.
Published: July 2021

Ecological or sensory system shifts associated with brain shape and size change may have contributed to unique avian survivorship.
Metabolic control of nitrogen fixation in rhizobium-legume symbioses
Authors: Schulte Carolin C. M. , Borah Khushboo , Wheatley Rachel M. , Terpolilli Jason J. , Saalbach Gerhard , Crang Nick , de Groot Daan H. , Ratcliffe R. George , Kruger Nicholas J. , Papachristodoulou Antonis , Poole Philip S.
Published: July 2021

Catabolism of dicarboxylates at low oxygen drives N
2
fixation and promotes ammonia secretion in rhizobium-legume symbioses.