bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics, pharmacodynamics, and exposure–efficacy of dupilumab in adults with atopic dermatitis
Authors: Kamal Mohamed A. , Davis John D. , Kovalenko Pavel , Srinivasan Kamal , Simpson Eric L. , Nakahara Takeshi , Sugaya Makoto , Igarashi Atsuyuki , Ardeleanu Marius , Xu Christine , Arima Kazuhiko 
Published: August 2022

AbstractThe pharmacokinetics (PKs) and exposure–efficacy of dupilumab have not been fully described for adults with atopic dermatitis (AD). Our objectives were to analyze the PKs and exposure–efficacy of dupilumab in adults with AD and compare the results of Japanese and overall populations. Adults with moderate‐to‐severe AD were randomly assigned to dupilumab (300 mg weekly [qw] or every 2 weeks [q2w], 200 mg q2w, 300 mg every 4 weeks [q4w], or 100 mg q4w) or placebo for 16 weeks in a randomized, double‐blind, placebo‐controlled, dose‐ranging phase IIb trial (NCT01859988). This analysis included 379 patients (58 Japanese). Functional dupilumab concentrations increased in a dose‐dependent manner; at lower concentrations, increases were greater than dose‐proportional because of nonlinear, target‐mediated clearance. Dupilumab pharmacokinetics were comparable in Japanese and non‐Japanese patients with similar body weights. Week 16 efficacy parameters, including Investigator’s Global Assessment score 0/1, greater than or equal to 75% reduction from baseline in the Eczema Area and Severity Index (EASI), and percentage change from baseline in EASI and pruritus Numerical Rating Scale, generally increased with week 16 trough concentration; the plateau of these exposure–efficacy relationships occurred for most patients at exposures associated with the 300 mg q2w and 300 mg qw regimens. Japanese ethnicity did not remain in the population PK model as covariate with or without accounting for body weight differences. In Japanese and non‐Japanese patients, efficacy responses increased with week 16 dupilumab trough concentrations in a similar manner. Dupilumab 300 mg qw and q2w regimens were recommended for further evaluation in larger phase III studies.
Global mortality of diabetic foot ulcer: A systematic review and meta‐analysis of observational studies
Authors: Chen Lihong , Sun Shiyi , Gao Yunyi , Ran Xingwu 
Published: August 2022

AbstractAimTo estimate the long‐term mortality and risk factors in patients with diabetic foot ulcer (DFU).MethodsWe systematically searched Medline (PubMed), Embase, Scopus, Web of Science, Cochrane Library, China Science and Technology Journal Database (CQVIP), China National Knowledge Infrastructure, the Chinese Biomedical Literature Database (SinoMed) and Wanfang Data from 1 January 2011 to 31 July 2022. All observational studies that reported long‐term mortality of patients with DFU were included. Random effect models were used to pool the reconstructed participant data from Kaplan–Meier curves. The primary outcome was the long‐term survival of patients with DFU. An aggregate data meta‐analysis was also performed.ResultsWe identified 34 studies, with 124 376 participants representing 16 countries, among whom there were 51 386 deaths. Of these, 27 studies with 21 171 patients were included in the Kaplan–Meier‐based meta‐analysis. The estimated Kaplan–Meier‐based survival rates were 86.9% (95% confidence interval [CI] 82.6%‐91.5%) at 1 year, 66.9% (95% CI 59.3%‐75.6%) at 3 years, 50.9% (95% CI 42.0%‐61.7%) at 5 years and 23.1% (95% CI 15.2%‐34.9%) at 10 years. The results of the aggregate data‐based meta‐analysis were similar. Cardiovascular disease and infection were the most common causes of death, accounting for 46.6% (95% CI 33.5%‐59.7%) and 24.8% (95% CI 16.0%‐33.5%), respectively. Patients with older age (per 1 year, hazard ratio [HR] 1.054, 95% CI 1.045‐1.063), peripheral artery disease (HR 1.882, 95% CI 1.592‐2.225), chronic kidney disease (HR 1.535, 95% CI 1.227‐1.919), end‐stage renal disease (HR 3.586, 95% CI 1.333‐9.643), amputation (HR 2.415, 95% CI 1.323‐4.408) and history of cardiovascular disease (HR 1.449, 95% CI 1.276‐1.645) had higher mortality risk.ConclusionsThis meta‐analysis found that the overall mortality of DFU was high, with nearly 50% mortality within 5 years. Cardiovascular disease and infection were the two leading causes of death.
Associations of microvascular complications with all‐cause death in patients with diabetes andCOVID‐19: TheCORONADO,ABCDCOVID‐19 UK national audit andAMERICADOstudy groups
Authors: Hadjadj Samy , Saulnier Pierre‐Jean , Ruan Yue , Zhu Xu , Pekmezaris Renee , Marre Michel , Halimi Jean Michel , Wargny Matthieu , Rea Rustam , Gourdy Pierre , Cariou Bertrand , Myers Alyson K. , Khunti Kamlesh ,   for the CORONADO, the ABCD COVID‐19 diabetes national audit and AMERICADO investigators
Published: August 2022

AbstractAimTo provide a detailled analysis of the microvascular burden in patients with diabetes hopitalized for COVD‐19.Materials and MethodsWe analysed data from the French CORONADO initiative and the UK Association of British Clinical Diabetologists (ABCD) COVID‐19 audit, two nationwide multicentre studies, and the AMERICADO, a multicentre study conducted in New York area. We assessed the association between risk of all‐cause death during hospital stay and the following microvascular complications in patients with diabetes hospitalized for COVID‐19: diabetic retinopathy and/or diabetic kidney disease and/or history of diabetic foot ulcer.ResultsAmong 2951 CORONADO, 3387 ABCD COVID‐19 audit and 9327 AMERICADO participants, microvascular diabetic complications status was ascertained for 1314 (44.5%), 1809 (53.4%) and 7367 (79.0%) patients, respectively: 1010, 1059 and 1800, respectively, had ≥1 severe microvascular complication(s) and 304, 750 and 5567, respectively, were free of any complications. The patients with isolated diabetic kidney disease had an increased risk of all‐cause death during hospital stay: odds ratio [OR] 2.53 (95% confidence interval [CI] 1.66‐3.83), OR 1.24 (95% CI 1.00‐1.56) and OR 1.66 (95% CI 1.40‐1.95) in the CORONADO, the ABCD COVID‐19 national audit and the AMERICADO studies, respectively. After adjustment for age, sex, hypertension and cardiovascular disease (CVD), compared to those without microvascular complications, patients with microvascular complications had an increased risk of all‐cause death during hospital stay in the CORONADO, the ABCD COVID‐19 diabetes national audit and the AMERICADO studies: adjusted OR (adjOR) 2.57 (95% CI 1.69‐3.92),adjOR 1.22 (95% CI 1.00‐1.52) andadjOR 1.33 (95% CI 1.15‐1.53), respectively. In meta‐analysis of the three studies, compared to patients free of complications, those with microvascular complications had an unadjusted OR for all‐cause death during hospital stay of 2.05 (95% CI 1.42‐2.97), which decreased to 1.62 (95% CI 1.19‐2.119) after adjustment for age and sex, and to 1.50 (1.12‐2.02) after hypertension and CVD were further added to the model.ConclusionMicrovascular burden is associated with an increased risk of death in patients hospitalized for COVID‐19.
Clinical implications of vascular dysfunction in acute and convalescent COVID‐19: A systematic review
Authors: Mavraganis Georgios , Dimopoulou Maria‐Angeliki , Delialis Dimitrios , Bampatsias Dimitrios , Patras Raphael , Sianis Alexandros , Maneta Eleni , Stamatelopoulos Kimon , Georgiopoulos Georgios 
Published: August 2022

AbstractBackgroundAccumulating evidence suggests that endothelial dysfunction is implicated in the pathogenesis and severity of coronavirus disease 2019 (COVID‐19). In this context, vascular impairment in COVID‐19 might be associated with clinical manifestations and could refine risk stratification in these patients.MethodsThis systematic review aims to synthesize current evidence on the frequency and the prognostic value of vascular dysfunction during acute and post‐recovery COVID‐19. After systematically searching the MEDLINE, clinicaltrials.gov and the Cochrane Library from 1 December 2019 until 05 March 2022, we identified 24 eligible studies with laboratory confirmed COVID‐19 and a thorough examination of vascular function. Flow‐mediated dilation (FMD) was assessed in 5 and 12 studies in acute and post‐recovery phase respectively; pulse wave velocity (PWV) was the marker of interest in three studies in the acute and four studies in the post‐recovery phase.ResultsAll studies except for one in the acute and in the post‐recovery phase showed positive association between vascular dysfunction and COVID‐19 infection. Endothelial dysfunction in two studies and increased arterial stiffness in three studies were related to inferior survival in COVID‐19.DiscussionOverall, a detrimental effect of COVID‐19 on markers of endothelial function and arterial stiffness that could persist even for months after the resolution of the infection and provide prognostic value was congruent across published studies. Further research is warranted to elucidate clinical implications of this association.
Ambulatory central BP and arterial stiffness in patients with and without intradialytic hypertension
Authors: Theodorakopoulou Marieta P. , Karagiannidis Artemios G. , Alexandrou Maria‐Eleni , Iatridi Fotini , Christodoulou Michalis , Dimitroulas Theodoros , Papagianni Aikaterini , Sarafidis Pantelis A. 
Published: August 2022

AbstractBackgroundIncreased arterial stiffness is suggested to be involved in the pathogenesis of intradialytic‐hypertension (IDH). Ambulatory pulse‐wave‐velocity (PWV) is an independent predictor for all‐cause‐mortality in haemodialysis and its prognostic power is better than office PWV. This is the first study examining ambulatory central blood pressure (BP) and arterial stiffness parameters in patients with and without IDH.MethodsThis study examined 45 patients with IDH (SBP rise ≥10 mmHg from pre‐ to post‐dialysis and post‐dialysis SBP ≥150 mmHg) in comparison with 197 patients without IDH. All participants underwent 48‐h ABPM with Mobil‐O‐Graph‐NG; parameters of central haemodynamics, wave reflection and PWV were estimated.ResultsAge, dialysis vintage and interdialytic weight gain did not differ between‐groups. IDH patients had higher 48‐h cSBP (131.7 ± 16.2 vs. 119.2 ± 15.2 mmHg, p < 0.001), 48‐h cDBP (86.7 ± 12.7 vs. 79.6 ± 11.5 mmHg, p < 0.001) and 48‐h cPP (45.5 ± 10.4 vs. 39.8 ± 10.0 mmHg, p = 0.001) compared to patients without IDH. Similarly, during day‐ and nighttime periods, cSBP/cDBP and cPP levels were higher in IDH‐patients compared to non‐IDH. Forty‐eight‐hour augmentation pressure and index, but not AIx(75) were higher in IDH patients; 48‐h PWV (10.0 ± 2.0 vs. 9.2 ± 2.1 m/s, p = 0.017) was significantly higher in patients with IDH. The two study groups displayed different trajectories in central BP and PWV over the course of the recording; IDH patients had steadily high values of the above variables during the 2 days of the interdialytic‐interval, whereas non‐IDH patients showed a gradual elevation, with significant increases from the 1st to 2nd 24 h.ConclusionsIDH patients have significantly higher levels of ambulatory central BP and arterial stiffness parameters and a different course over the 48‐h period compared with non‐IDH patients. Increased arterial stiffness could be a prominent factor associated with the high burden of cardiovascular disease in this population.
Life history adaptations to fluctuating environments: Combined effects of demographic buffering and lability
Authors: Le Coeur Christie , Yoccoz Nigel G. , Salguero‐Gómez Roberto , Vindenes Yngvild 
Published: August 2022

AbstractDemographic buffering and lability have been identified as adaptive strategies to optimise fitness in a fluctuating environment. These are not mutually exclusive, however, we lack efficient methods to measure their relative importance for a given life history. Here, we decompose the stochastic growth rate (fitness) into components arising from nonlinear responses and variance–covariance of demographic parameters to an environmental driver, which allows studying joint effects of buffering and lability. We apply this decomposition for 154 animal matrix population models under different scenarios to explore how these main fitness components vary across life histories. Faster‐living species appear more responsive to environmental fluctuations, either positively or negatively. They have the highest potential for strong adaptive demographic lability, while demographic buffering is a main strategy in slow‐living species. Our decomposition provides a comprehensive framework to study how organisms adapt to variability through buffering and lability, and to predict species responses to climate change.
The EICA is dead? Long live the EICA!
Authors: Callaway Ragan M. , Lucero Jacob E. , Hierro José L. , Lortie C. J. 
Published: August 2022

AbstractAn important hypothesis for how plants respond to introduction to new ranges is the evolution of increased competitive ability (EICA). EICA predicts that biogeographical release from natural enemies initiates a trade‐off in which exotic species in non‐native ranges become larger and more competitive, but invest less in consumer defences, relative to populations in native ranges. This trade‐off is exceptionally complex because detecting concomitant biogeographical shifts in competitive ability and consumer defence depends upon which traits are targeted, how competition is measured, the defence chemicals quantified, whether defence chemicals do more than defend, whether ‘herbivory’ is artificial or natural, and where consumers fall on the generalist‐specialist spectrum. Previous meta‐analyses have successfully identified patterns but have yet to fully disentangle this complexity. We used meta‐analysis to reevaluate traditional metrics used to test EICA theory and then expanded on these metrics by partitioning competitive effect and competitive tolerance measures and testing Leaf‐Specific Mass in detail as a response trait. Unlike previous syntheses, our meta‐analyses detected evidence consistent with the classic trade‐off inherent to EICA. Plants from non‐native ranges imposed greater competitive effects than plants from native ranges and were less quantitatively defended than plants from native ranges. Our results for defence were not based on complex leaf chemistry, but instead were estimated from tannins, toughness traits and primarily Leaf‐Specific Mass. Species specificity occurred but did not influence the general patterns. As for all evidence for EICA‐like trade‐offs, we do not know if the biogeographical differences we found were caused by trade‐offs per se, but they are consistent with predictions derived from the overarching hypothesis. Underestimating physical leaf structure may have contributed to two decades of tepid perspectives on the trade‐offs fundamental to EICA.
Eco‐evolutionary dynamics of interference competition
Authors: Grether Gregory F. , Okamoto Kenichi W. 
Published: August 2022

AbstractTheorists have identified several mechanisms through which species that compete exploitatively for resources could coexist. By contrast, under the current theory, interference competitors could coexist only in rare circumstances. Yet, some types of interference competition, such as interspecific territoriality, are common. This mismatch between theory and nature inspired us to model interference competition in an eco‐evolutionary framework. We based the model on the life cycle of territorial birds and ran simulations to examine whether natural selection could rescue a superior interference competitor from extinction without driving a superior exploitative competitor extinct. We found that coexistence between interference competitors can occur over a wide range of ecologically plausible scenarios, and up to the highest levels of resource overlap. An important caveat is that coexistence requires the species to co‐evolve. Reductions in population size and levels of genetic variation could destabilise coexistence between interference competitors, and thereby increase extinction rates over current estimates.
GluN2C selective inhibition is a target to develop new antiepileptic compounds
Authors: Gataullina Svetlana , Galvani Gilles , Touchet Sabrina , Nous Caroline , Lemaire Éric , Laschet Jacques , Chiron Catherine , Dulac Olivier , Dossi Elena , Brion Jean‐Daniel , Messaoudi Samir , Alami Mouad , Huberfeld Gilles 
Published: August 2022

AbstractObjectiveMany early‐onset epilepsies present as developmental and epileptic encephalopathy associated with refractory seizures, altered psychomotor development, and disorganized interictal cortical activity. Abnormal upregulation of specific N‐methyl‐d‐aspartate receptor (NMDA‐R) subunits is being disentangled as one of the mechanisms of severe early‐onset epilepsies. In tuberous sclerosis complex (TSC), upregulation of the GluN2C subunit of the NMDA‐R with slow deactivation kinetic results in increased neuronal excitation and synchronization.MethodsStarting from an available GluN2C/D antagonist, NMDA‐R–modulating compounds were developed and screened using a patch clamp on neuronal culture to select those with the strongest inhibitory effect on glutamatergic NMDA currents. For these selected compounds, blood pharmacokinetics and passage through the blood–brain barrier were studied. We tested the effect of the most promising compounds on epileptic activity in Tsc1+/− mice brain slices with multielectrode array, and then in vivo at postnatal ages P14–P17, comparable with the usual age at epilepsy onset in human TSC.ResultsUsing a double‐electrode voltage clamp on isolated NMDA currents, we identified the most prominent antagonists of the GluN2C subunit with no effect on GluN2A as a means of preventing side effects. The best compound passing through the blood–brain barrier was selected. Applied in vivo in six Tsc1+/− mice at P14–P17, this compound reduced or completely stopped spontaneous seizures in four of them, and decreased the background activity disorganization. Furthermore, ictal‐like discharges stopped on a human brain sample from an infant with epilepsy due to TSC.InterpretationSubunit‐selective inhibition is a valuable target for developing drugs for severe epilepsies resulting from an upregulation of NMDA‐R subunit–mediated transmission.
Contrasting population genetic responses to migration barriers in two native and an invasive freshwater fish
Authors: Deflem Io S. , Calboli Federico C. F. , Christiansen Henrik , Hellemans Bart , Raeymaekers Joost A. M. , Volckaert Filip A. M. 
Published: August 2022

AbstractHabitat fragmentation impacts the distribution of genetic diversity and population genetic structure. Therefore, protecting the evolutionary potential of species, especially in the context of the current rate of human‐induced environmental change, is an important goal. In riverine ecosystems, migration barriers affect the genetic structure of native species, while also influencing the spread of invasive species. In this study, we compare genetic patterns of two native and one highly invasive riverine fish species in a Belgian river basin, namely the native three‐spined stickleback (Gasterosteus aculeatus) and stone loach (Barbatula barbatula), and the non‐native and invasive topmouth gudgeon (Pseudorasbora parva). We aimed to characterize both natural and anthropogenic determinants of genetic diversity and population genetic connectivity. Genetic diversity was highest in topmouth gudgeon, followed by stone loach and three‐spined stickleback. The correlation between downstream distance and genetic diversity, a pattern often observed in riverine systems, was only marginally significant in stone loach and three‐spined stickleback, while genetic diversity strongly declined with increasing number of barriers in topmouth gudgeon. An Isolation‐By‐Distance pattern characterizes the population genetic structure of each species. Population differentiation was only associated with migration barriers in the invasive topmouth gudgeon, while genetic composition of all species seemed at least partially determined by the presence of migration barriers. Among the six barrier types considered (watermills, sluices, tunnels, weirs, riverbed obstructions, and others), the presence of watermills was the strongest driver of genetic structure and composition. Our results indicate that conservation and restoration actions, focusing on conserving genetic patterns, cannot be generalized across species. Moreover, measures might target either on restoring connectivity, while risking a rapid spread of the invasive topmouth gudgeon, or not restoring connectivity, while risking native species extinction in upstream populations.
Introduction to special section: Federally funded, community‐based healthy marriage and responsible fatherhood program impact studies
Authors: Rhoades Galena K. , Doss Brian D. , Carlson Ryan G. 
Published: August 2022

AbstractThe focus of this special section is impact studies that were conducted as part of the Administration for Children and Families' Healthy Marriage and Responsible Fatherhood initiative. This initiative has led to more than 2 million people receiving relationship education and fatherhood programs across the United States over the last two decades. Community organizations develop these programs, select their curricula and content, and run these programs in their local communities. Many programs funded in the 2015–2020 cohort of grantees included randomized controlled trials of program effectiveness; some of these studies are presented in this issue, with the goal of marrying the field of program evaluation and family science.
Sex‐specific role of the circadian transcription factor NPAS2 in opioid tolerance, withdrawal and analgesia
Authors: Puig Stephanie , Shelton Micah A. , Barko Kelly , Seney Marianne L. , Logan Ryan W. 
Published: August 2022

AbstractOpioids like fentanyl remain the mainstay treatment for chronic pain. Unfortunately, opioid's high dependence liability has led to the current opioid crisis, in part, because of side‐effects that develop during long‐term use, including analgesic tolerance and physical dependence. Both tolerance and dependence to opioids may lead to escalation of required doses to achieve previous therapeutic efficacy. Additionally, altered sleep and circadian rhythms are common in people on opioid therapy. Opioids impact sleep and circadian rhythms, while disruptions to sleep and circadian rhythms likely mediate the effects of opioids. However, the mechanisms underlying these bidirectional relationships between circadian rhythms and opioids remain largely unknown. The circadian protein, neuronal PAS domain protein 2 (NPAS2), regulates circadian‐dependent gene transcription in structure of the central nervous system that modulate opioids and pain. Here, male and female wild‐type and NPAS2‐deficient (NPAS2−/−) mice were used to investigate the role of NPAS2 in fentanyl analgesia, tolerance, hyperalgesia and physical dependence. Overall, thermal pain thresholds, acute analgesia and tolerance to a fixed dose of fentanyl were largely similar between wild‐type and NPAS2−/− mice. However, female NPAS2−/− exhibited augmented analgesic tolerance and significantly more behavioral symptoms of physical dependence to fentanyl. Only male NPAS2−/− mice had increased fentanyl‐induced hypersensitivity, when compared with wild‐type males. Together, our findings suggest sex‐specific effects of NPAS2 signaling in the regulation of fentanyl‐induced tolerance, hyperalgesia and dependence.