bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of hydroxycarbamide treatment on the whole‐blood transcriptome in sickle cell disease
Authors: Bhat Varsha , Potdar Alka A. , Yu G. Karen , Gibson Greg , Sheehan Vivien A. 
Published: November 2024

SummaryHydroxycarbamide (HC) is the most widely used therapeutic for individuals with sickle cell disease (SCD, including sickle cell anemia and other forms of the disease). HC's clinical benefits are primarily associated with its ability to induce foetal haemoglobin (HbF); this limited view of HC's therapeutic potential may lead to its discontinuation when a modest amount of HbF is induced. A better understanding of the HbF‐independent effects of HC on genes and pathways relevant to SCD pathophysiology is therefore needed. In this study, we performed bulk RNA‐Seq on whole blood samples collected from a cohort of 25 paediatric patients with SCD to identify genes and pathways that are affected by treatment with HC. At the maximum tolerated dose (MTD) of HC, patients showed altered expression levels of several genes and biological pathways. Pathways related to haeme metabolism, interferon‐alpha response, and interferon‐gamma response were significantly downregulated at HC MTD relative to the matched pre‐HC samples. Pathways linked with IL2‐STAT5 signalling and TNFα signalling via NF‐Kβ were observed to be up‐regulated at HC MTD. These results illustrate the range of effects exerted by HC during therapy for SCD and pave the way for an improved understanding of the HbF induction‐independent benefits of HC.
Inhibition of FcRn with rozanolixizumab in adults with immune thrombocytopenia: Two randomised, double‐blind, placebo‐controlled phase 3 studies and their open‐label extension
Authors: Cooper Nichola , Bussel James B. , Kaźmierczak Maciej , Miyakawa Yoshitaka , Cluck Sarah , Lledó García Rocío , Haier Birgit , Lavrov Andreea , Singh Puneet , Snipes Rose , Kuter David J. 
Published: November 2024

SummaryPrimary immune thrombocytopenia (ITP) is an antiplatelet‐antibody‐mediated disorder with accelerated platelet clearance and decreased platelet production. Rozanolixizumab, a monoclonal IgG4 anti‐FcRn antibody, blocks IgG recycling and decreases IgG levels. We report efficacy and safety of rozanolixizumab in adults with persistent/chronic ITP in 24‐week phase 3 studies (TP0003; TP0006), and their 52‐week open‐label extension (OLE). Primary end‐point was durable clinically meaningful platelet response (DCMPR) of ≥50 × 109/L for 8/12 weeks during Weeks 13–25 in the double‐blind studies. Operational delays and evolving ITP treatment landscape led the sponsor to terminate these studies early; thus, only 21 and 12 (TP0003) and 20 and 10 (TP0006) patients were randomised to rozanolixizumab or placebo. Forty‐three patients enrolled in the OLE: 42 started on every 2‐week dosing; 21 later switched to weekly dosing. More rozanolixizumab‐treated than placebo‐treated patients achieved DCMPR: 4/21 versus 0 (TP0003) and 1/20 versus 0 (TP0006). Platelet increases to ≥50 × 109/L were observed on Day 8 in 52.4% (TP0003; 2/12 placebo) and 45.0% (TP0006; 1/10 placebo) of rozanolixizumab‐treated patients. OLE platelet increases were maintained while on weekly dosing. The most frequent treatment‐emergent adverse events overall were headache, pyrexia and nausea, as seen previously. Weekly dosing appears more efficacious than every 2‐week dosing.
Alone together? A time use approach for examining socializing when travel is limited
Authors: DeJohn Amber , Liu Bochu , Ma Xinlin , Widener Michael J. , Liu Zhilin 
Published: November 2024

AbstractMigrant populations access different social networks due to their cultural contexts and the locations of their social relationships. The COVID‐19 pandemic generated concern about social isolation among older adults. During Ontario's extended lockdown, we investigated the social behaviours of a generally sedentary older Chinese migrant community (n = 77) in the Greater Toronto Area. Using single‐day activity diaries, we grouped respondents using a k‐means clustering approach, which resulted in four categories of socializing characteristics. We then used ANOVA tests and multinomial logistic regression to understand the geographic contexts for these socializing behaviours. Findings reveal that this older migrant community was mostly socializing online, but a small group reported socializing in person. Living in a house, having better physical health, and having children living abroad was associated with a higher likelihood of socializing in person rather than online. Ultimately, it is important to understand the context within which older migrants socialize in order to support social connection and related health outcomes as they age.
Parents spontaneously scaffold the formation of conversational pacts with their children
Authors: Leung Ashley , Yurovsky Daniel , Hawkins Robert D. 
Published: November 2024

AbstractAdults readily coordinate on temporary pacts about how to refer to things in conversation. Young children are also capable of forming pacts with peers given appropriate experimenter intervention. Here, we investigate whether parents may spontaneously provide a similar kind of scaffolding with U.S. children in a director–matcher task (N = 201, 49% female; ages 4, 6, 8). In Experiment 1, we show that parents initiate more clarification exchanges with younger children who, in turn, are more likely to adopt labels introduced by the parent. We then examine whether the benefit of such scaffolding acts primarily through childrens' difficulties with comprehension (Experiment 2) or production (Experiment 3). Our findings suggest that parents primarily scaffold pacts by easing children's production difficulties, modeling cooperative communication.
BRCC3‐Associated Syndromic Moyamoya Angiopathy Diagnosed Through Clinical RNA Sequencing
Authors: Venema Myrrhe , Albuainain Fatimah , Schot Rachel , Roozenbeek Bob , Sleutels Frank , van Ham Tjakko , Barakat Tahsin Stefan 
Published: November 2024

ABSTRACTMoyamoya angiopathy is a cerebral vasculopathy causing progressive stenosis of the internal carotid arteries and the compensatory development of collateral blood vessels, leading to brain ischemia and an increased risk of cerebral haemorrhage. Although multiple non‐genetic causes have been associated with moyamoya syndrome, it can also be associated with rare genetic syndromes. Moyamoya Disease 4, characterised by a short stature, hypergonadotropic hypogonadism and facial dysmorphism (MYMY4, OMIM #300845), also referred to as BRCC3‐associated moyamoya syndrome, has so far been described in 11 individuals. Here, we describe a 23‐year‐old male presenting with moyamoya syndrome, global developmental delay and intellectual disability, epilepsy, short stature and dysmorphic features, who after > 17 years of uninformative diagnostics was diagnosed with BRCC3‐associated moyamoya syndrome after clinical RNA‐seq. Transcriptome analysis showed reduced expression of the likely disease‐causing gene BRCC3 in patient‐derived fibroblasts, which was subsequently found to be caused by a ~ 26 kb Xq28 deletion. We furthermore review all reported cases of BRCC3‐associated moyamoya syndrome, further delineating this clinical entity.
Lay Theories of Moral Progress
Authors: Lewry Casey , Asifriyaz Sana , Lombrozo Tania 
Published: November 2024

AbstractMany consider the world to be morally better today than it was in the past and expect moral improvement to continue. How do people explain what drives this change? In this paper, we identify two ways people might think about how moral progress occurs: that it is driven by human action (i.e., if people did not actively work to make the world better, moral progress would not occur) or that it is driven by an unspecified mechanism (i.e., that our world is destined to morally improve, but without specifying a role for human action). In Study 1 (N = 147), we find that those who more strongly believe that the mechanism of moral progress is human action are more likely to believe their own intervention is warranted to correct a moral setback. In Study 2 (N = 145), we find that this translates to intended action: those who more strongly believe moral progress is driven by human action report that they would donate more money to correct a moral setback. In Study 3 (N = 297), participants generate their own explanations for why moral progress occurs. We find that participants’ donation intentions are predicted by whether their explanations state that human action drives moral progress. Together, these studies suggest that beliefs about the mechanisms of moral progress have important implications for engaging in social action.
Current and future climate suitability for the hazel dormouse in the UK and the impact on reintroduced populations
Authors: Cartledge Emma L. , Bellis Joe , White Ian , Hurst Jane L. , Stockley Paula , Dalrymple Sarah 
Published: November 2024

AbstractReintroductions are increasingly being used as a conservation tool to restore species to areas where they once existed. Unfortunately, many reintroduction projects fail to establish viable populations. Climate suitability at release sites is thought to be important in determining reintroduction outcomes, and future climate change is an essential consideration for effective reintroduction planning. Climate change threatens species in a variety of ways, such as by impacting life history traits or causing spatial and temporal distribution mismatches of interdependent species. Hibernating species, such as the hazel dormouse (Muscardinus avellanarius), may be particularly susceptible to changes in climate. For example, milder winters may increase the number of interbout arousals during hibernation, which are energetically costly. Timing of food availability may also be impacted by changing climates, potentially causing mismatches between activity and feeding opportunities. Here, we use species distribution models (SDMs) to map climate suitability for dormice in the UK. We also investigate the impact of climate suitability on a long‐running dormouse reintroduction programme, providing the first such investigation for a reintroduced mammal. We find that higher levels of current climate suitability increase the probability of reintroduction success. We find no effect of climate suitability on adult dormouse counts at reintroduction sites, but dormouse counts decline with time since reintroduction. Future projections predict that climate change may lead to more widespread climate suitability for dormice in the UK, reflecting predicted changes in seasonality, winter temperature and precipitation. Our work demonstrates the importance of understanding changing climate suitability for reintroduction planning, with potential widespread applications of SDMs for conservation projects of low‐dispersing mammals.
Calcineurin‐Inhibitor Discontinuation Could Reduce the Risk of De Novo Malignancies After Liver Transplantation for Alcohol‐Related Liver Disease
Authors: Erard Domitille , Steiner Anouk , Boillot Olivier , Thimonier Elsa , Vallin Mélanie , Veyre Florian , Guillaud Olivier , Radenne Sylvie , Dumortier Jérôme 
Published: November 2024

ABSTRACTBackgroundDe novo malignancies are one of the leading causes of death after liver transplantation (LT), particularly in patients transplanted for alcohol‐related liver disease (ALD). This retrospective study aimed to assess risk factors for malignancies and to evaluate the impact of calcineurin inhibitor (CNI) discontinuation.MethodsFrom 1990 to 2015, all patients transplanted for ALD were included.ResultsA total of 493 patients were included, 77.9% were male and the median age at LT was 54 years. After LT, 278 de novo malignancies were diagnosed in 214 patients (43.4%). The cumulative incidence of de novo malignancies was 16.3% at 5 years, 34.4% at 10 years, and 49.8% at 15 years. In multivariate analysis, the independent risk factors were male gender (HR = 1.6), and active or weaned smoking (HR = 2.0). Discontinuation of CNI was a protective factor (HR = 0.6). Survival after diagnosis of de novo malignancy was 42.7% at 5 years and 27.5% at 10 years.ConclusionOur results confirm the major incidence of de novo malignancies after LT for ALD, as well as the important role of non‐modifiable risk factors such as smoking and gender. CNI discontinuation is a protective factor, and the only adaptable, and could be proposed in smoker male patients transplanted for ALD.
Imetelstat, a novel, first‐in‐class telomerase inhibitor: Mechanism of action, clinical, and translational science
Authors: Lennox Ashley L. , Huang Fei , Behrs Melissa Kelly , González‐Sales Mario , Bhise Neha , Wan Ying , Sun Libo , Berry Tymara , Feller Faye , Morcos Peter N. 
Published: November 2024

AbstractMost cancers and neoplastic progenitor cells have elevated telomerase activity and preservation of telomeres that promote cellular immortality, making telomerase a rational target for the treatment of cancer. Imetelstat is a first‐in‐class, 13‐mer oligonucleotide that binds with high affinity to the template region of the RNA component of human telomerase and acts as a competitive inhibitor of human telomerase enzymatic activity. Pharmacokinetics, pharmacodynamics, exposure‐response analyses, efficacy, and safety of imetelstat have been evaluated in vitro, in vivo, and clinically in solid tumor and hematologic malignancies, including lower‐risk myelodysplastic syndromes (LR‐MDS) and myeloproliferative neoplasms. Imetelstat was approved in the United States in June 2024 for the treatment of adult patients with LR‐MDS with transfusion‐dependent anemia requiring four or more red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis‐stimulating agents, with a recommended dosing regimen of 7.1 mg/kg administered via 2‐h intravenous infusion every 4 weeks. In the pivotal trial, significantly more patients treated with imetelstat versus placebo achieved ≥8‐week and ≥24‐week red blood cell‐transfusion independence, and imetelstat was associated with a manageable safety profile characterized primarily by short‐lived and manageable neutropenia and thrombocytopenia. This mini‐review summarizes the mechanism of action, pharmacokinetic and pharmacodynamic characteristics, clinical development, and clinical efficacy and safety data of imetelstat.
Efficacy and safety of tofacitinib in rheumatoid arthritis: Nine years of real‐world data
Authors: Ekin Ali , Misirci Salim , İldemir Selin , Coskun Belkıs Nihan , Yagiz Burcu , Dalkilic Ediz , Pehlivan Yavuz 
Published: November 2024

AbstractTofacitinib is a targeted JAK inhibitor used to treat rheumatoid arthritis. Despite some recent safety concerns, it is considered effective and safe with appropriate patient selection. Between May 2015 and May 2024, data were retrospectively analyzed from 112 patients with a diagnosis of RA in a tertiary care hospital who had received tofacitinib for at least 1 month, with or without prior biologic DMARDs. The mean disease duration was 12 years, and the median duration of tofacitinib use was 32.5 months. The p‐value for all disease activity parameters evaluated for effectiveness between the 1st‐ and 3rd‐month visits was <0.001, except CRP (p = 0.097). Adverse events occurred in 15 (13.4%) patients, with an incidence rate of 4.54 per 100 patient‐years. Observed were one myocardial infarction (0.3/100 patient‐years), two pulmonary embolisms (0.6/100 patient‐years), three herpes zoster (HZ) (0.9/100 patient‐years), and one basal cell carcinoma (BCC) (0.3/100 patient‐years). Median drug‐free survival was 68 (95% CI: 54.8–81.2) months. The drug was discontinued in 28 (25%) patients due to ineffectiveness and in 13 (11.6%) due to side effects. A significant difference in drug survival rates was observed between patients who had not previously used bDMARDs and those who had received at least one bDMARD before tofacitinib (p < 0.001). Drug survival was 46.35 months in the prior bDMARD group and 71.09 months in the bDMARD‐naive group. This study found significant reductions in disease activity indices at 3 and 6 months after starting tofacitinib, with sustained effectiveness. Although adverse event rates were somewhat higher than reported in the literature, tofacitinib can be used effectively and safely in appropriate patient populations for RA treatment.
The right to counsel: criminal prosecution in 19th century London
Authors: McCannon Bryan C. , Porreca Zachary 
Published: November 2024

AbstractWe exploit a dataset of criminal trials in 19th century London to evaluate the impact of an accused's right to counsel on convictions. While lower‐level crimes had an established history of professional representation prior to 1836, individuals accused of committing a felony did not, despite the prosecution being conducted by professional attorneys. The Prisoners' Counsel Act 1836 remedied this and first introduced the right to counsel in common law systems. Using a difference‐in‐differences estimation strategy, we identify the effect of the universal right to defence counsel. We find the surprising result that the professionalization of the courtroom led to an increase in the conviction rate. We argue that this effect was a consequence of the Act inducing a shift in the beliefs of jurors, who grew more likely to believe the evidence put before them once it could be challenged in an adversarial courtroom. We go further, and employ a topic modelling approach to the text of the transcripts to provide suggestive evidence on how the trials changed when the right to defence counsel was fully introduced, documenting a movement towards increased usage of precise and detailed language when discussing details of alleged offences.
Parenthood and occupational mobility
Authors: Liu Andrew Yizhou 
Published: November 2024

AbstractI show that parenthood contributes to the downward‐sloping age‐occupational‐mobility profile. After the birth of the first child, men experience a 20% decline in occupational switching which is uniform across upward and downward mobility. For women, the decline is 14%, which is larger for upward than for downward occupational mobility. Therefore, parenthood can explain 22% and 12% of the declines in occupational mobility for working men and women between 25 and 45 years of age, respectively. Workers in disadvantaged groups experience larger decreases, highlighting the potential impacts of parenthood on their occupational choices.
Teaching Controversial Issues under Conditions of Political Polarization: A Case for Epistemic Refocusing
Authors: Torres Eric 
Published: November 2024

AbstractEducating students for democratic life requires teachers to make difficult judgment calls about whether controversial issues are appropriate for directive teaching (i.e., teaching that attempts to persuade students to adopt a particular view about the thing being taught). To help educators make these decisions, theorists have proposed criteria for systematically differentiating between issues that do and do not qualify for directive teaching. Unfortunately, the epistemic environment of political polarization degrades educators' abilities to reliably assess whether a broad class of politically contested issues meet these criteria for directive teaching. In this paper Eric Torres argues that, while making judgments about whether individual cases warrant directive teaching remains essential and inevitable, educators can best address this problem by engaging in a practice of epistemic refocusing that makes the conditions of educators' own deliberations salient to students, thereby hedging against the effects of bad calls about which issues to teach directively while simultaneously illuminating the constraints of polarization on political cognition, an awareness that is essential to healthy democratic participation in the twenty‐first century.
Effect of masticatory muscle function on the craniofacial sutures of the anterior viscerocranium in growing rats
Authors: Gorucu‐Coskuner Hande , Al‐Yassary Mustafa , Billiaert Kelly , Kiliaridis Stavros , Antonarakis Gregory S. 
Published: November 2024

AbstractThe transverse dimensions of internasal and nasopremaxillary sutures in rats were assessed at different ages and following different dietary functional demands.Eighty‐four male Wistar rats were divided into two groups fed either a hard or a soft diet from 4 weeks of age, and sacrificed at 4 weeks (baseline: n = 12),16 weeks (n = 24), 26 weeks (n = 24), or 38 weeks (n = 24) of age. High‐resolution micro‐computed tomograms of the internasal and left nasopremaxillary sutures were obtained with 10 µm voxel size and 5 × 5 mm field of view. The endocranial and ectocranial suture widths, the mean suture width, and the suture height were measured. Linear regression analysis was used to estimate the effects of age and type of diet on suture dimensions. Internasal and nasopremaxillary suture dimensions were influenced by age, with a generally lower width and a larger height in the older animal. Regarding diet consistency, internasal suture widths were on average larger in the hard‐diet group (e.g., mean suture width 43 µm in the hard‐ versus 30 µm in the soft‐diet group at 26 weeks). In conclusion, the internasal and nasopremaxillary sutures tend to become narrower with age, while being influenced by masticatory functional demands.
Interleukin‐33 Deficiency Protects the Skin From Ulcer Formation in an Ischemia–Reperfusion‐Induced Decubitus Mouse Model
Authors: Jin Meijuan , Komine Mayumi , Tsuda Hidetoshi , Sashikawa‐Kimura Miho , Nakae Susumu , Motegi Sei‐ichiro , Ohtsuki Mamitaro 
Published: November 2024

ABSTRACTInterleukin‐33 (IL‐33) is an alarmin released upon epithelial tissue damage. It functions as a nuclear factor for regulating gene expression. We hypothesised that IL‐33 is involved in the formation of decubitus ulcers through damaged epidermis. Therefore, this study aimed to clarify the mechanism of IL‐33 action in decubitus ulcer formation. IL‐33 knockout (KO), soluble stimulation‐2 (ST2) transgenic, and wild‐type (WT) mice were used to construct an ischemia–reperfusion (I/R) injury as a decubitus model. The ulcer area was significantly reduced in IL‐33 KO mice compared to WT mice but was not reduced in ST2 transgenic mice. Anti‐IL‐33 receptor (transmembrane ST2) antibodies effectively prevented ulcer formation; however, an anti‐IL‐33 neutralising antibody was ineffective. The number of infiltrating macrophages was higher, while that of neutrophils and mast cells was lower in IL‐33 KO mice than in WT mice. The number of M2 macrophages increased in IL‐33 KO mice. Characterisation of gene expression levels revealed significantly reduced interleukin‐1 beta (IL‐1β) and increased C‐C motif chemokine ligand 17 expression in IL‐33 KO mice. Macrophages isolated from ulcers in WT or IL‐33 KO mice stimulated with exogenous IL‐33 produced comparable amounts of IL‐1β. In conclusion, our study indicates that IL‐33 is released in response to I/R injury in the skin, contributing to inflammatory macrophage and mast cell infiltration and stimulation, resulting in IL‐1β production and the massive infiltration of effector cells, including neutrophils, which finally induces decubitus ulcer formation. These results suggest that suppressing IL‐33 expression could be beneficial for treating early‐phase decubitus ulcers.