bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long‐Term Creatine Supplementation Improves Cognitive and Hippocampal Structural Plasticity Impairments in a D‐Gal‐Induced Aging Model via Increasing CK‐BB Activity in the Brain
Authors: Zhu Zhu , Zhang Hantao , Li Qianlin , Han Xu , Wang Tiantian , Zhang Wenjing , Chen Feiyan , Gu Ling , Yao Qi , Chen Lin , Zhao Yunan 
Published: January 2025

ABSTRACTCreatine (Cr) is recognized for its role in enhancing cognitive functions through the phosphocreatine (pCr)–creatine kinase system involved in brain energy homeostasis. It is reversibly converted into pCr by creatine kinase (CK). A brain‐specific isoform of CK, known as CK‐BB, is implicated in the brain's energy metabolism. The objective of this research is to ascertain the impact of Cr supplementation on learning and memory skills as well as on structural synaptic plasticity, by modulating CK‐BB. First, we utilized various concentrations of D‐galactose (D‐gal) to create an aging mouse model. Our findings indicated that D‐gal injections at 100 and 1000 mg/kg could lead to cognitive decline, oxidative stress, and damage to structural synaptic plasticity. CK‐BB expression and its activity were reduced at least by approximately 20% in mice injected with 100 and 1000 mg/kg D‐gal compared with control group. Next, an adeno‐associated virus directed against CKB was employed to reduce CK‐BB levels by 34% in the brain. The reduction of CK‐BB in the brain resulted in deficits in learning and memory, oxidative stress, and morphological harm to the hippocampal spines of mice. Finally, the diet of the D‐gal‐induced aging model was enriched with 3% Cr. Mice that received 3% Cr supplementation exhibited a 36% increase in CK‐BB activity and a 14.3% increase in CK‐BB expression following prolonged D‐gal administration. In addition, Cr supplementation mitigated the cognitive impairment, oxidative stress, and hippocampal structural plasticity damage caused by chronic D‐gal injections. Overall, our study revealed that CK‐BB has a critical role in mediating structural plasticity in D‐gal‐induced cognitive impairment. Moreover, it showed that supplementary Cr could serve as a potent neuroprotective substance, preventing or delaying the course of age‐related cognitive deficits.
Multivariable MR Can Mitigate Bias in Two‐Sample MR Using Covariable‐Adjusted Summary Associations
Authors: Gilbody Joe , Borges Maria Carolina , Davey Smith George , Sanderson Eleanor 
Published: January 2025

ABSTRACTGenome‐wide association studies (GWAS) are hypothesis‐free studies that estimate the association between polymorphisms across the genome with a trait of interest. To increase power and to estimate the direct effects of these single‐nucleotide polymorphisms (SNPs) on a trait GWAS are often conditioned on a covariate (such as body mass index or smoking status). This adjustment can introduce bias in the estimated effect of the SNP on the trait. Two‐sample Mendelian randomisation (MR) studies use summary statistics from GWAS estimate the causal effect of a risk factor (or exposure) on an outcome. Covariate adjustment in GWAS can bias the effect estimates obtained from MR studies conducted using covariate adjusted GWAS data. Multivariable MR (MVMR) is an extension of MR that includes multiple traits as exposures. Here we propose the use of MVMR to correct the bias in MR studies from covariate adjustment. We show how MVMR can recover unbiased estimates of the direct effect of the exposure of interest by including the covariate used to adjust the GWAS within the analysis. We apply this method to estimate the effect of systolic blood pressure on type‐2 diabetes and the effect of waist circumference on systolic blood pressure. Our analytical and simulation results show that MVMR provides unbiased effect estimates for the exposure when either the exposure or outcome of interest has been adjusted for a covariate. Our results also highlight the parameters that determine when MR will be biased by GWAS covariate adjustment. The results from the applied analysis mirror these results, with equivalent results seen in the MVMR with and without adjusted GWAS. When GWAS results have been adjusted for a covariate, biasing MR effect estimates, direct effect estimates of an exposure on an outcome can be obtained by including that covariate as an additional exposure in an MVMR estimation. However, the estimated effect of the covariate obtained from the MVMR estimation is biased.
Assessing Cigarette Reduction Tax‐Effectiveness in Low Tobacco Expenditure Contexts: An Application to Bolivia
Authors: Morales Joaquín , Santander Sara 
Published: January 2025

ABSTRACTIn this research we show that ambitious increases in tobacco tax rates can substantially reduce tobacco consumption, increase fiscal revenue, and provide net positive social benefits even in contexts of low consumption prevalence and intensity. Low nicotine intake still constitutes a grave disease risk factor, and the effectiveness of tax increases might be questioned if income effects are small. We adapt spatial variation of price methodologies to deal with low prevalence and intensity, censored data, and small samples using the Bolivian case as an illustration. We find an average price elasticity of demand of to . Using our estimates of elasticities, we develop a simulation to anticipate the effects of a 35% yearly increase of the Bolivian specific excise on tobacco starting in 2025. Our estimates show that by 2030, this reform could reduce the consumption of cigarettes by 52.6%, diminish the prevalence of smoking by 30.6%, and increase fiscal revenue by $123 million over six years. Moreover, we estimate that the abated direct medical costs of reduced consumption net of the deadweight loss associated with a tax increase would generate a net social gain of over $100 million in five years.
Value‐Based Pricing for Drugs With Uncertain Clinical Benefits
Authors: Jiao Boshen , Hsieh Yuli Lily , Li Meng , Verguet Stéphane 
Published: January 2025

ABSTRACTPolicymakers can use cost‐effectiveness analysis to set value‐based prices (VBP) for new pharmaceuticals. However, the uncertainty of investigational drug benefits complicates this pricing strategy. Such complexity stems from decision‐makers' risk aversion and the potential change in the estimated value with emerging evidence. The recent surge in drugs approved via the Accelerated Approval (AA) pathway in the U.S. has made incorporating uncertainty into VBP crucial. We propose to estimate risk‐adjusted VBP (rVBP) for drugs with uncertain benefits via integrating value of information and expected utility theory. Our approach involves two assessment points: an initial assessment with existing evidence; and a reassessment with new evidence that reduces uncertainty. This approach enables decision‐makers to set rVBP in the initial assessment such that the expected utility, from the exisiting evidence, aligns with the benchmark uncertainty. We evaluate two benchmarks: one with no uncertainty, and one with a decision‐maker's acceptable uncertainty level. We show in a case study of a hypothetical AA drug that rVBP may be lower than traditional VBP, especially under high risk aversion or low acceptable uncertainty. Our methodology adjusts VBP to account for uncertainty, supporting decision‐makers in balancing timely market access with the risks associated with uncertainty in the benefits of new pharmaceuticals.
Impact of myelodysplasia‐related and additional gene mutations in intensively treated patients with NPM1‐mutated AML
Authors: Cocciardi Sibylle , Saadati Maral , Weiß Nina , Späth Daniela , Kapp‐Schwoerer Silke , Schneider Isabelle , Meid Annika , Gaidzik Verena I. , Skambraks Sabrina , Fiedler Walter , Kühn Michael W. M. , Germing Ulrich , Mayer Karin T. , Lübbert Michael , Papaemmanuil Elli , Thol Felicitas , Heuser Michael , Ganser Arnold , Bullinger Lars , Benner Axel , Döhner Hartmut , Döhner Konstanze 
Published: January 2025

ABSTRACTThis study aimed to evaluate the impact of the myelodysplasia‐related gene (MRG) as well as additional gene mutations on outcomes in intensively treated patients with NPM1‐mutated (NPM1mut) AML. Targeted DNA sequencing of 263 genes was performed in 568 NPM1mut AML patients (median age: 59 years) entered into the prospective AMLSG 09‐09 treatment trial. Most commonly co‐mutated genes were DNMT3A (49.8%), FLT3‐TKD (25.9%), PTPN11 (24.8%), NRAS (22.7%), TET2 (21.7%), IDH2 (21.3%), IDH1 (18%), and FLT3‐ITD (17.3%). MRG mutations were identified in 18.1% of cases (18–60 years: 9.8%; >60 years: 28.7%). When focusing on the 470 patients with 2022 ELN favorable‐risk NPM1mut AML, multivariable analysis for event‐free survival (EFS) identified age (p < 0.001), DNMT3AR882 (p < 0.001), IDH1 (p = 0.007), and MRG mutations (p = 0.03) as unfavorable factors, cohesin gene co‐mutations (p = 0.001) and treatment with gemtuzumab ozogamicin (p = 0.007) as favorable factors. Restricting the analysis to a subset of CR/CRi patients with available data on NPM1mut measurable residual disease (MRD) status in blood post cycle 2 in the model, MRG mutations lost their significant effect, whereas DNMT3AR882, MYC, and cohesin gene mutations retained the adverse and favorable effects. For OS, age (p < 0.001), DNMT3AR882 (p = 0.042), IDH1 (p = 0.045), and KRAS (0.003) mutations were unfavorable factors, sole favorable factor was IDH2 co‐mutation (p = 0.037). In 2022 ELN favorable‐risk NPM1mut AML, MRG mutations are associated with inferior EFS; however, this effect is no longer present when considering NPM1mut MRD status post cycle 2; DNMT3AR882 and MYC mutations remained adverse, and cohesin gene mutations favorable prognostic factors independent of the NPM1mut MRD status.
Successful Pregnancies During Crizotinib Therapy for Anaplastic Lymphoma Kinase Positive Lymphoma
Authors: Guglielmana Veronica , Fusi Francesco Maria , Giardini Valentina , Cocito Federica , Gambacorti‐Passerini Carlo 
Published: January 2025

ABSTRACTAnaplastic lymphoma kinase positive (ALK+) anaplastic large cell lymphoma (ALCL) typically affects young individuals and, despite high responsiveness to cytotoxic drugs, relapses occur in over 50% of patients. Crizotinib has improved outcomes, but its management in patients desiring parenthood remains an issue. This study presents the first description of four successful pregnancies during crizotinib treatment for ALK+ALCL: a female patient achieving two pregnancies through assisted reproductive technologies (ART), temporarily discontinuing crizotinib and maintaining a complete remission (CR), and a male patient conceiving naturally while on continuous therapy. These cases demonstrate crizotinib potential to support conception without compromising disease control, even in the absence of specific guidelines on treatment discontinuation.
Portal‐Vein Compression Caused by Double‐Pigtail Plastic Biliary Stent
Authors: Akiyama Shinsuke , Wada Masaya , Inokuma Tetsuro 
Published: January 2025

ABSTRACTIntroductionReports of pseudoaneurysms associated with biliary self‐expandable metallic stent (SEMS) placement have been increasing. Recently, cases of hepatic pseudoaneurysm rupture caused by double pigtail plastic stents (DPS) have also been reported. The symptoms of pseudoaneurysms are often non‐specific, and many cases are diagnosed only after rupture. Therefore, early detection and appropriate treatment are required.Case PresentationA 45‐year‐old woman presented with obstructive jaundice caused by pancreatic head cancer, with imaging revealing common bile duct stenosis and intrahepatic bile duct dilation. Endoscopic retrograde cholangiopancreatography (ERCP) was performed to place a DPS in the left hepatic duct, relieving jaundice. However, follow‐up contrast‐enhanced computed tomography (CE‐CT) revealed differences in arterial‐phase blood flow between the liver lobes without reduction in portal vein blood flow. Therefore, the compression and stenosis of the left branch of the portal vein caused by the DPS were clearly identified using three‐dimensional computed tomography (3D‐CT). The DPS was replaced with a straight‐type stent, preventing further complications. The patient subsequently underwent successful pancreaticoduodenectomy without any surgical complications.ConclusionThis is a case of portal vein compression caused by double‐pigtail plastic biliary stent. By promptly recognizing the differences in arterial‐phase blood flow between the liver lobes and replacing the DPS with a straight‐type plastic stent, complications, such as portal vein pseudoaneurysm formation, rupture, embolism, or thrombosis, were successfully avoided.
Comparative Evaluation of Three Rapid Influenza Diagnostic Tests for Detection of Influenza A and B Viruses Using RT‐PCR as Reference Method
Authors: Yin Hailun , Wu Wenjuan , Lv Yuyang , Kou Hanlin , Sun Yuzhen 
Published: January 2025

ABSTRACTTo evaluate the performance of three rapid influenza diagnostic tests (RIDTs) for detecting influenza A and B viruses compared to RT‐PCR. A total of 291 subjects with acute respiratory infections were enrolled. Respiratory specimens were collected and tested for influenza A and B viruses using three RIDTs. The results were compared with those obtained using an RT‐PCR assay from Shanghai Berger Medical Technology Co. Ltd. as the reference method. Among the 291 subjects, 119 (40.9%) tested positive for influenza A virus and 38 (13.1%) for influenza B virus by RT‐PCR. The sensitivities of the three RIDTs for influenza A virus were 92.4%, 89.1%, and 79.8%, respectively, while their specificities were 98.8%, 98.8%, and 100%, respectively. For influenza B virus, the sensitivities of the three RIDTs were 92.1%, 92.1%, and 73.7%, respectively, and their specificities were 100%, 100%, and 100%, respectively. The positive predictive values (PPVs) for influenza A virus were 98.2%, 98.1%, and 100%, respectively, while the negative predictive values (NPVs) were 94.5%, 92.4%, and 86.9%, respectively. For influenza B virus, the PPVs were all 100%, and the NPVs were 99.2%, 99.2%, and 97.7%, respectively. The three evaluated RIDTs demonstrated high specificity but varied sensitivity for detecting influenza A and B viruses. Negative results from RIDTs should be confirmed by RT‐PCR, especially during peak influenza seasons. The high PPVs suggest that positive RIDT results are reliable for influenza diagnosis, while the high NPVs indicate that negative results are more likely to be true negatives.
A record of monsoon rainforest variability from the Kimberley region in northwestern Australia
Authors: Rudd Rachel C. , Dixon Teresa , Callow John Nikolaus , Gadd Patricia S. , Maizma Sabika , Jacobsen Geraldine , Moss Patrick , McGowan Hamish 
Published: January 2025

ABSTRACTNorthern Australia experiences extreme seasonality via the Indo‐Australian summer monsoon, with high inter‐annual variability in hydroclimate. Understanding the influence of hydrological variability on the landscape through the period of human occupation provides important environmental context to support the interpretation of the rich archaeological and rock art records of the region. The development of terrestrial records of environmental change has remained challenging due to the limited traditional palaeoenvironmental archives in the region. This study reports on the potential of sediments from ecologically significant monsoon rainforest patches to further elucidate the palaeoenvironmental history of the Kimberley. An ~19 000‐year record of monsoon rainforest variability is presented, inferred from pollen, charcoal and major element geochemical analysis. Monsoon rainforest‐associated taxa vary in abundance through the deglacial and the Holocene, which is compared to broad‐scale hydroclimate variability inferred from previous studies in the region. The persistence of arboreal, riparian and monsoon rainforest‐associated taxa suggest a positive moisture balance at the site throughout the period archived. Fire activity inferred from micro‐ and macrocharcoal is greatest over the last ~6000 years, and broadly corresponds to periods when monsoon rainforest‐associated taxa are less abundant. Challenges remain in using this type of site as an archive of environmental change, but they also present an opportunity to extend previous records both spatially and temporally with thousands of monsoon rainforest patches present across the Kimberley, and similar ecosystems found across northern Australia.
Cold Water Swimming and Pregnancy: A Scoping Review and Consensus Recommendations
Authors: Shawe J , Felton M , Harper JC , Harper C Mark , Stidson R , Tipton M , Blowers S , Fraser K , Hingley S , McGrath E , Bainbridge G , Heather Massey 
Published: January 2025

ABSTRACTIntroductionCold water swimming has increased in popularity and women wish to swim throughout pregnancy. There is a lack of evidenced‐based guidance to make decisions about the safety of immersion in cold water during pregnancy.MethodsClosed social media groups were asked for specific questions in relation to cold water swimming and pregnancy. This highlighted concerns including water temperature, risks to the mother and fetus, and water quality. To find evidence‐based answers, a series of meetings brought together clinicians and researchers with expertise in cold water physiology, exercise physiology, fertility, obstetrics, neonatology, midwifery, water epidemiology, public health and representatives from the Open Water Swimming Society and an Open Water swimming social enterprise.ResultsPublished data were examined via a scoping review process and four studies and eight reports were identified. Recommendations were made with evidence graded (mostly grade 4 expert opinion).ConclusionResearch gaps highlight the need for research to enable accurate advice to determine whether it is safe for pregnant women to swim outdoors in cold water.
Validity and Reliability of the Arabic Cough Severity Index
Authors: Alrabiah Hamad F. , Alqarni Nawaf , Alrajhi Nuha , Basfar Aban , Mesallam Tamer A. , Farahat Mohamed , Malki Khalid H. 
Published: January 2025

ABSTRACTObjectivesThis study aimed to translate and validate the Cough Severity Index (CSI) into Arabic (A‐CSI) and to evaluate its validity and reliability among patients with chronic cough.MethodsThis cross‐sectional descriptive questionnaire‐based validation study was conducted at two tertiary hospitals in Riyadh, Saudi Arabia, between December 2023 and August 2024. The CSI was translated from English into Arabic using the forward‐backward method. Its reliability was assessed using Cronbach's alpha and test–retest reliability. Its construct validity was assessed using exploratory factor analysis (EFA), and its internal consistency was assessed using Cronbach's alpha. Its discriminant validity was determined using the Mann–Whitney U test, and its reproducibility was evaluated using the intraclass correlation coefficient (ICC).ResultsData were collected from 100 participants, 50 with chronic cough and 50 healthy controls. The mean age was 41.56 ± 14.28 years in the chronic cough group and 35.48 ± 10.02 years in the healthy control group. The A‐CSI exhibited high reproducibility (ICC = 0.896) and excellent internal consistency (Cronbach's alpha = 0.966). EFA identified three factors explaining 66.41% of the variance, with all items having communalities > 0.3. The A‐CSI exhibited significant discriminant validity between the chronic cough and healthy control groups (p < 0.001).ConclusionThe A‐CSI is a reliable and valid tool for assessing chronic cough in Arabic‐speaking patients, making it suitable for both clinical practice and research.Level of EvidenceLevel 3.
The Long‐Term Effect of Childhood Otitis Media on Speech‐in‐Noise Testing at Ages 9 and 13
Authors: Reijers Stefanie N. H. , Vroegop Jantien L. , Kremer Bernd , van der Schroeff Marc P. 
Published: January 2025

ABSTRACTObjectiveTo investigate the relationship between a history of otitis media (OM) in early childhood and speech reception thresholds (SRT) in later childhood, using the Dutch digits‐in‐noise (DIN) test at ages 9 and 13 years.MethodsThis study was conducted within the Generation R study, a prospective birth cohort in Rotterdam, the Netherlands. Children underwent pure‐tone audiometry and DIN testing at ages 9 (2011–2015) and 13 (2016–2020) years. Regression analyses and a linear mixed model were used to examine associations between OM history and SRT in noise, accounting for repeated measurements within individuals.ResultsAt baseline (age 9 years), 2063 children were included with a mean SRT of −5.6 (SD = 2.0). At follow‐up (age 13 years), 3382 children were included with a mean SRT of −7.4 (SD = 1.4). A positive association was found between recurrent acute OM (RAOM) and DIN test outcomes, with an estimated coefficient of 0.55 (95% CI = 0.26, 0.84; t‐value = 3.70). Socioeconomic status and multilingualism did not significantly predict DIN test performance.ConclusionA history of RAOM may potentially influence SRT outcomes in later childhood, with higher DIN scores observed in the RAOM group. While the effect sizes between the groups are small to moderate, these findings highlight the importance of considering the potential long‐term effects of OM in both clinical practice and future research. Further studies are needed to better understand these relationships.Level of Evidence2 (cohort study).
Advances in moyamoya disease: pathogenesis, diagnosis, and therapeutic interventions
Authors: He Shihao , Zhou Zhenyu , Cheng Michelle Y. , Hao Xiaokuan , Chiang Terrance , Wang Yanru , Zhang Junze , Wang Xilong , Ye Xun , Wang Rong , Steinberg Gary K. , Zhao Yuanli 
Published: January 2025

AbstractMoyamoya disease (MMD) is a type of cerebrovascular disease characterized by occlusion of the distal end of the internal carotid artery and the formation of collateral blood vessels. Over the past 20 years, the landscape of research on MMD has significantly transformed. In this review, we provide insights into the pathogenesis, diagnosis, and therapeutic interventions in MMD. The development of high‐throughput sequencing technology has expanded our understanding of genetic susceptibility, identifying MMD‐related genes beyond RNF213, such as ACTA2, DIAPH1, HLA, and others. The genetic susceptibility of MMD to its pathological mechanism was summarized and discussed. Based on the second‐hit theory, the influences of inflammation, immunity, and environmental factors on MMD were also appropriately summarized. Despite these advancements, revascularization surgery remains the primary treatment for MMD largely because of the lack of effective in vivo and in vitro models. In this study, 16 imaging diagnostic methods for MMD were summarized. Regarding therapeutic intervention, the influences of drugs, endovascular procedures, and revascularization surgeries on patients with MMD were discussed. Future research on the central MMD vascular abnormalities and peripheral circulating factors will provide a more comprehensive understanding of the pathogenic mechanisms of MMD.
Structural and Dynamic Assessment of Disease‐Causing Mutations for the Carnitine Transporter OCTN2
Authors: Jokiel Johannes , Bermudez Marcel 
Published: January 2025

AbstractPrimary carnitine deficiency (PCD) is a rare autosomal recessive genetic disorder caused by missense mutations in the SLC22A5 gene encoding the organic carnitine transporter novel type 2 (OCTN2). This study investigates the structural consequences of PCD‐causing mutations, focusing on the N32S variant. Using an alpha‐fold model, molecular dynamics simulations reveal altered interactions and dynamics suggesting potential mechanistic changes in carnitine transport. In addition, we identify mutation hotspots (R169, E452) across the SLC family with the major facilitator superfamily (MFS) fold. Our data demonstrates the applicability of structural modeling for linking genetic information and clinical observations and providing a rationale for the influence of disease‐causing mutations on protein dynamics.