bluuebunny/crossref_metadata_2025_split huggingface dataset:
Additional mutation inPROKR2and phenotypic differences in a Kallmann syndrome/normosmic congenital hypogonadotropic hypogonadism family carryingFGFR1missense mutation
Authors: Ichioka Kentaro , Yoshikawa Takeshi , Kimura Hiroko , Saito Ryoichi 
Published: January 2024

Congenital hypogonadotropic hypogonadism (CHH) is a genetically and clinically diverse disorder encompassing Kallmann syndrome (KS) and normosmic CHH (nCHH). Although mutations in numerous genes account for nearly 50% of CHH cases, a significant portion remains genetically uncharacterized. While most mutations follow the traditional Mendelian inheritance patterns, evidence suggests oligogenic interactions between CHH genes, acting as modifier genes to explain variable expressivity and incomplete penetrance associated with certain mutations.In this study, the proband presented with nCHH, while his son exhibited KS. We employed whole-exome sequencing (WES) to investigate the genetic differences between the two, and Sanger sequencing was used to validate the results obtained from WES.Genetic analysis revealed that both the proband and his son harboured a mutation inFGFR1gene. Notably, an additional rare mutation inPROKR2gene was exclusively identified in the son, which suggests the cause of the phenotypic difference between KS and nCHH.
Incident dementia risk among patients with type 2 diabetes receiving metformin versus alternative oral glucose-lowering therapy: an observational cohort study using UK primary healthcare records
Authors: Doran William , Tunnicliffe Louis , Muzambi Rutendo , Rentsch Christopher T , Bhaskaran Krishnan , Smeeth Liam , Brayne Carol , Williams Dylan M , Chaturvedi Nish , Eastwood Sophie V , Dunachie Susanna J , Mathur Rohini , Warren-Gash Charlotte 
Published: January 2024

Introduction4.2 million individuals in the UK have type 2 diabetes, a known risk factor for dementia and mild cognitive impairment (MCI). Diabetes treatment may modify this association, but existing evidence is conflicting. We therefore aimed to assess the association between metformin therapy and risk of incident all-cause dementia or MCI compared with other oral glucose-lowering therapies (GLTs).Research design and methodsWe conducted an observational cohort study using the Clinical Practice Research Datalink among UK adults diagnosed with diabetes at ≥40 years between 1990 and 2019. We used an active comparator new user design to compare risks of dementia and MCI among individuals initially prescribed metformin versus an alternative oral GLT using Cox proportional hazards regression controlling for sociodemographic, lifestyle and clinical confounders. We assessed for interaction by age and sex. Sensitivity analyses included an as-treated analysis to mitigate potential exposure misclassification.ResultsWe included 211 396 individuals (median age 63 years; 42.8% female), of whom 179 333 (84.8%) initiated on metformin therapy. Over median follow-up of 5.4 years, metformin use was associated with a lower risk of dementia (adjusted HR (aHR) 0.86 (95% CI 0.79 to 0.94)) and MCI (aHR 0.92 (95% CI 0.86 to 0.99)). Metformin users aged under 80 years had a lower dementia risk (aHR 0.77 (95% CI 0.68 to 0.85)), which was not observed for those aged ≥80 years (aHR 0.95 (95% CI 0.87 to 1.05)). There was no interaction with sex. The as-treated analysis showed a reduced effect size compared with the main analysis (aHR 0.90 (95% CI 0.83 to 0.98)).ConclusionsMetformin use was associated with lower risks of incident dementia and MCI compared with alternative GLT among UK adults with diabetes. While our findings are consistent with a neuroprotective effect of metformin against dementia, further research is needed to reduce risks of confounding by indication and assess causality.
Multimodal profiling of chordoma immunity reveals distinct immune contextures
Authors: van Oost Siddh , Meijer Debora M , Ijsselsteijn Marieke E , Roelands Jessica P , van den Akker Brendy E M W , van der Breggen Ruud , Briaire-de Bruijn Inge H , van der Ploeg Manon , Wijers-Koster Pauline M , Polak Samuel B , Peul Wilco C , van der Wal Robert J P , de Miranda Noel F C C , Bovee Judith V M G 
Published: January 2024

BackgroundChordomas are rare cancers from the axial skeleton which present a challenging clinical management with limited treatment options due to their anatomical location. In recent years, a few clinical trials demonstrated that chordomas can respond to immunotherapy. However, an in-depth portrayal of chordoma immunity and its association with clinical parameters is still lacking.MethodsWe present a comprehensive characterization of immunological features of 76 chordomas through application of a multimodal approach. Transcriptomic profiling of 20 chordomas was performed to inform on the activity of immune-related genes through the immunologic constant of rejection (ICR) signature. Multidimensional immunophenotyping through imaging mass cytometry was applied to provide insights in the different immune contextures of 32 chordomas. T cell infiltration was further evaluated in all 76 patients by means of multispectral immunofluorescence and then associated with clinical parameters through univariate and multivariate Cox proportional hazard models as well as Kaplan-Meier estimates. Moreover, distinct expression patterns of human leukocyte antigen (HLA) class I were assessed by immunohistochemical staining in all 76 patients. Finally, clonal enrichment of the T cell receptor (TCR) was sought through profiling of the variable region ofTCRBlocus of 24 patients.ResultsChordomas generally presented an immune “hot” microenvironment in comparison to other sarcomas, as indicated by the ICR transcriptional signature. We identified two distinct groups of chordomas based on T cell infiltration which were independent from clinical parameters. The highly infiltrated group was further characterized by high dendritic cell infiltration and the presence of multicellular immune aggregates in tumors, whereas low T cell infiltration was associated with lower overall cell densities of immune and stromal cells. Interestingly, patients with higher T cell infiltration displayed a more pronounced clonal enrichment of the TCR repertoire compared with those with low T cell counts. Furthermore, we observed that the majority of chordomas maintained HLA class I expression.ConclusionOur findings shed light on the natural immunity against chordomas through the identification of distinct immune contextures. Understanding their immune landscape could guide the development and application of immunotherapies in a tailored manner, ultimately leading to an improved clinical outcome for patients with chordoma.
ON/OFF non-motor evaluation: a new way to evaluate non-motor fluctuations in Parkinson’s disease
Authors: Faggianelli Florent , Witjas Tatiana , Azulay J-P , Benatru Isabelle , Hubsch Cécile , Anheim Mathieu , Moreau Caroline , Hainque Elodie , Drapier Sophie , Jarraya Béchir , Laurencin Chloé , Guehl Dominique , Hopes Lucie , Brefel-Courbon Christine , Tir Melissa , Marques Ana , Rouaud Tiphaine , Maltete David , Giordana Caroline , Baumstarck Karine , Rascol Olivier , Corvol Jean Christophe , Rolland Anne-Sophie , Devos David , Eusebio Alexandre 
Published: January 2024

Background
NMF are currently poorly evaluated in therapeutic decisions. A quantification of their severity would facilitate their integration. The objective of this study was to validate an autoquestionnaire evaluating the severity of non-motor fluctuations (NMF) in Parkinson’s disease (PD).

Methods
Patients with PD were included in presurgical situation for deep brain stimulation of subthalamic nuclei. They participated in the PREDISTIM cohort (a study evaluating the predictive factors for therapeutic response of subthalamic stimulation in PD) in 17 centres in France. Our questionnaire, resulting from previous phases of development, included 11 non-motor symptoms (NMS). Their severity ranged from 0 to 10 and was assessed in OFF and then ON-Dopa to study their fluctuations.

Results
310 patients were included, of whom 98.8% had NMS and 98.0% had NMF. Each NMS was significantly improved by L-Dopa (decrease in severity score ranging from 43.1% to 69.9%). Fatigue was the most frequent and most severe NMS. NMS were considered more bothersome than motor symptoms by 37.5% of patients in OFF-Dopa and 34.9% in ON-Dopa.

Conclusions
This is the first questionnaire allowing a real-time quantification of the severity of NMS and their fluctuation with levodopa. It was able to confirm and measure the effect of L-dopa and show differences according to the patients and the NMS. It differs from other questionnaires by its measurement at a precise moment of the severity of the NMS, allowing its use during pretherapeutic assessments.
Our questionnaire has been validated to measure the severity of NMF. It will be able to quantify the non-motor effect of anti-parkinsonian treatments and could facilitate the integration of NMF in therapeutic decisions.
Comparison of methods to identify individuals prescribed opioid analgesics for pain
Authors: Farjo Reem , Hu Hsou-Mei , Waljee Jennifer F , Englesbe Michael J , Brummett Chad M , Bicket Mark C 
Published: January 2024

IntroductionWhile identifying opioid prescriptions in claims data has been instrumental in informing best practises, studies have not evaluated whether certain methods of identifying opioid prescriptions yield better results. We compared three common approaches to identify opioid prescriptions in large, nationally representative databases.MethodsWe performed a retrospective cohort study, analyzing MarketScan, Optum, and Medicare claims to compare three methods of opioid classification: claims database-specific classifications, National Drug Codes (NDC) from the Centers for Disease Control and Prevention (CDC), or NDC from Overdose Prevention Engagement Network (OPEN). The primary outcome was discrimination by area under the curve (AUC), with secondary outcomes including the number of opioid prescriptions identified by experts but not identified by each method.ResultsAll methods had high discrimination (AUC>0.99). For MarketScan (n=70,162,157), prescriptions that were not identified totalled 42,068 (0.06%) for the CDC list, 2,067,613 (2.9%) for database-specific categories, and 0 (0%) for the OPEN list. For Optum (n=61,554,852), opioid prescriptions not identified totalled 9,774 (0.02%) for the CDC list, 83,700 (0.14%) for database-specific categories, and 0 (0%) for the OPEN list. In Medicare claims (n=92,781,299), the number of opioid prescriptions not identified totalled 8,694 (0.01%) for the CDC file and 0 (0%) for the OPEN list.DiscussionThis analysis found that identifying opioid prescriptions using methods from CDC and OPEN were similar and superior to prespecified database-specific categories. Overall, this study shows the importance of carefully selecting the approach to identify opioid prescriptions when investigating claims data.
Vector Biology and Integrated Management of Malaria Vectors in China
Authors: Zhao Tongyan , Xue Rui-De 
Published: January 2024

Malaria is an infectious disease caused by Plasmodium parasites, transmitted by Anopheles sinensis, Anopheles lesteri, Anopheles minimus, and Anopheles dirus in China. In 2021, the disease was eliminated in China after more than 70 years of efforts implementing an integrated mosquito management strategy. This strategy comprised indoor residual spray, insecticide-treated bed nets, irrigation management, and rice–fish coculture based on an understanding of taxonomic status and ecological behaviors of vector species, in conjunction with mass drug administration and promotion of public education. However, China still faces postelimination challenges, including the importation of approximately 2,000–4,000 cases of malaria into the country each year, as well as widespread resistance to pyrethroid insecticides in An. sinensis; these challenges require long-term vector surveillance to understand the distribution, population density, and development of resistance in vector mosquitoes to prevent local epidemics caused by imported malaria cases.
Human Tumor–Associated Macrophages and Neutrophils Regulate Antitumor Antibody Efficacy through Lethal and Sublethal Trogocytosis
Authors: Singhal Sunil , Rao Abhishek S. , Stadanlick Jason , Bruns Kyle , Sullivan Neil T. , Bermudez Andres , Honig-Frand Adam , Krouse Ryan , Arambepola Sachinthani , Guo Emily , Moon Edmund K. , Georgiou George , Valerius Thomas , Albelda Steven M. , Eruslanov Evgeniy B. 
Published: January 2024

Abstract

The clinical benefits of tumor-targeting antibodies (tAb) are modest in solid human tumors. The efficacy of many tAbs is dependent on Fc receptor (FcR)–expressing leukocytes that bind Fc fragments of tAb. Tumor-associated macrophages (TAM) and neutrophils (TAN) represent the majority of FcR+ effectors in solid tumors. A better understanding of the mechanisms by which TAMs and TANs regulate tAb response could help improve the efficacy of cancer treatments. Here, we found that myeloid effectors interacting with tAb-opsonized lung cancer cells used antibody-dependent trogocytosis (ADT) but not antibody-dependent phagocytosis. During this process, myeloid cells “nibbled off” tumor cell fragments containing tAb/targeted antigen (tAg) complexes. ADT was only tumoricidal when the tumor cells expressed high levels of tAg and the effectors were present at high effector-to-tumor ratios. If either of these conditions were not met, which is typical for solid tumors, ADT was sublethal. Sublethal ADT, mainly mediated by CD32hiCD64hi TAM, led to two outcomes: (i) removal of surface tAg/tAb complexes from the tumor that facilitated tumor cell escape from the tumoricidal effects of tAb; and (ii) acquisition of bystander tAgs by TAM with subsequent cross-presentation and stimulation of tumor-specific T-cell responses. CD89hiCD32loCD64lo peripheral blood neutrophils (PBN) and TAN stimulated tumor cell growth in the presence of the IgG1 anti-EGFR Ab cetuximab; however, IgA anti-EGFR Abs triggered the tumoricidal activity of PBN and negated the stimulatory effect of TAN. Overall, this study provides insights into the mechanisms by which myeloid effectors mediate tumor cell killing or resistance during tAb therapy.

Significance:
The elucidation of the conditions and mechanisms by which human FcR+ myeloid effectors mediate cancer cell resistance and killing during antibody treatment could help develop improved strategies for treating solid tumors.
Single-Cell RNA-Seq Reveals Coronary Heterogeneity and Identifies CD133
+
TRPV4
high
Endothelial Subpopulation in Regulating Flow-Induced Vascular Tone in Mice
Authors: Mao Aiqin , Zhang Ka , Kan Hao , Gao Mengru , Wang Zhiwei , Zhou Tingting , Shao Jing , He Dongxu 
Published: January 2024

BACKGROUND:
Single-cell RNA-Seq analysis can determine the heterogeneity of cells between different tissues at a single-cell level. Coronary artery endothelial cells (ECs) are important to coronary blood flow. However, little is known about the heterogeneity of coronary artery ECs, and cellular identity responses to flow. Identifying endothelial subpopulations will contribute to the precise localization of vascular endothelial subpopulations, thus enabling the precision of vascular injury treatment.

METHODS:
Here, we performed a single-cell RNA sequencing of 31 962 cells and functional assays of 3 branches of the coronary arteries (right coronary artery/circumflex left coronary artery/anterior descending left coronary artery) in wild-type mice.

RESULTS:

We found a compendium of 7 distinct cell types in mouse coronary arteries, mainly ECs, granulocytes, cardiac myocytes, smooth muscle cells, lymphocytes, myeloid cells, and fibroblast cells, and showed spatial heterogeneity between arterial branches. Furthermore, we revealed a subpopulation of coronary artery ECs, CD133
+
TRPV4
high
ECs. TRPV4 (transient receptor potential vanilloid 4) in CD133
+
TRPV4
high
ECs is important for regulating vasodilation and coronary blood flow.

CONCLUSIONS:

Our study elucidates the nature and range of coronary arterial cell diversity and highlights the importance of coronary CD133
+
TRPV4
high
ECs in regulating coronary vascular tone.
Diacylglycerols and Lysophosphatidic Acid, Enriched on Lipoprotein(a), Contribute to Monocyte Inflammation
Authors: Dzobo Kim E. , Cupido Arjen J. , Mol Barend M. , Stiekema Lotte C.A. , Versloot Miranda , Winkelmeijer Maaike , Peter Jorge , Pennekamp Anne-Marije , Havik Stefan R. , Vaz Frédéric M. , van Weeghel Michel , Prange Koen H.M. , Levels Johannes H.M. , de Winther Menno P.J. , Tsimikas Sotirios , Groen Albert K. , Stroes Erik S.G. , de Kleijn Dominique P.V. , Kroon Jeffrey 
Published: January 2024

BACKGROUND:
Oxidized phospholipids play a key role in the atherogenic potential of lipoprotein(a) (Lp[a]); however, Lp(a) is a complex particle that warrants research into additional proinflammatory mediators. We hypothesized that additional Lp(a)-associated lipids contribute to the atherogenicity of Lp(a).

METHODS:
Untargeted lipidomics was performed on plasma and isolated lipoprotein fractions. The atherogenicity of the observed Lp(a)-associated lipids was tested ex vivo in primary human monocytes by RNA sequencing, ELISA, Western blot, and transendothelial migratory assays. Using immunofluorescence staining and single-cell RNA sequencing, the phenotype of macrophages was investigated in human atherosclerotic lesions.

RESULTS:

Compared with healthy individuals with low/normal Lp(a) levels (median, 7 mg/dL [18 nmol/L]; n=13), individuals with elevated Lp(a) levels (median, 87 mg/dL [218 nmol/L]; n=12) demonstrated an increase in lipid species, particularly diacylglycerols (DGs) and lysophosphatidic acid (LPA). DG and the LPA precursor lysophosphatidylcholine were enriched in the Lp(a) fraction. Ex vivo stimulation with DG(40:6) demonstrated a significant upregulation in proinflammatory pathways related to leukocyte migration, chemotaxis, NF-κB (nuclear factor kappa B) signaling, and cytokine production. Functional assessment showed a dose-dependent increase in the secretion of IL (interleukin)-6, IL-8, and IL-1β after DG(40:6) and DG(38:4) stimulation, which was, in part, mediated via the NLRP3 (NOD [nucleotide-binding oligomerization domain]-like receptor family pyrin domain containing 3) inflammasome. Conversely, LPA-stimulated monocytes did not exhibit an inflammatory phenotype. Furthermore, activation of monocytes by DGs and LPA increased their transendothelial migratory capacity. Human atherosclerotic plaques from patients with high Lp(a) levels demonstrated colocalization of Lp(a) with M1 macrophages, and an enrichment of CD68
+
IL-18
+
TLR4
+
(toll-like receptor) TREM2
+
(triggering receptor expressed on myeloid cells) resident macrophages and CD68
+
CASP1
+
(caspase) IL-1B
+
SELL
+
(selectin L) inflammatory macrophages compared with patients with low Lp(a). Finally, potent Lp(a)-lowering treatment (pelacarsen) resulted in a reduction in specific circulating DG lipid subspecies in patients with cardiovascular disease with elevated Lp(a) levels (median, 82 mg/dL [205 nmol/L]).

CONCLUSIONS:
Lp(a)-associated DGs and LPA have a potential role in Lp(a)-induced monocyte inflammation by increasing cytokine secretion and monocyte transendothelial migration. This DG-induced inflammation is, in part, NLRP3 inflammasome dependent.
Estimation of Distribution Algorithm for Grammar-Guided Genetic Programming
Authors: Criado Pablo Ramos , Rolanía D. Barrios , de la Hoz David , Manrique Daniel 
Published: January 2024

Abstract
Genetic variation operators in grammar-guided genetic programming are fundamental to guide the evolutionary process in search and optimization problems. However, they show some limitations, mainly derived from an unbalanced exploration and local-search trade-off. This paper presents an estimation of distribution algorithm for grammar-guided genetic programming to overcome this difficulty and thus increase the performance of the evolutionary algorithm. Our proposal employs an extended dynamic stochastic context-free grammar to encode and calculate the estimation of the distribution of the search space from some promising individuals in the population. Unlike traditional estimation of distribution algorithms, the proposed approach improves exploratory behavior by smoothing the estimated distribution model. Therefore, this algorithm is referred to as SEDA, smoothed estimation of distribution algorithm. Experiments have been conducted to compare overall performance using a typical genetic programming crossover operator, an incremental estimation of distribution algorithm, and the proposed approach after tuning their hyperparameters. These experiments involve challenging problems to test the local search and exploration features of the three evolutionary systems. The results show that grammar-guided genetic programming with SEDA achieves the most accurate solutions with an intermediate convergence speed.
Socratic Heterodoxy? Ontological Commitment in the Hippias Major
Authors: Driscoll Sean 
Published: January 2024

Abstract
The question of ontological commitment in Plato’s Hippias Major has been important in disputes over the dialogue’s place in the corpus, its meaning, and its authenticity. But this question seems to have been settled—the Hippias Major is not committed to the ‘forms.’ Such an ontological conclusion has been vigorously defended, but its defenses rest on a problematic meta-ontological framework. This paper suggests a more adequate framework and brings more evidence to the evaluation of the question of ontological commitment in the Hippias Major. It concludes that the dialogue is indeed committed to some kind of form.
Bringing Climate Change to Strasbourg. The Convention and Healthy Environment Claims
Authors: den Exter André 
Published: January 2024

Abstract
Climate change profoundly impacts all aspects of human life, including health. International fora and nation States recognise the importance of urgently cutting greenhouse gas emissions as a primary cause of global warming. States’ commitment to alter climate change has resulted in several treaty documents referring explicitly to human rights obligations. But what exactly are States’ obligations under climate change treaty law and other human rights treaties? And what is the judiciary’s role when confronted with the right to health violations and systemic deficiencies relating to climate change? Can climate change litigation give individual citizens a remedy to right to health violations and reduce the impact of climate change?
Research on the Lacquered Channel Figurine Excavated from a Han Tomb in Tianhui
Authors: Zhou Qi , Yu Catherine Xin Xin 
Published: January 2024

Abstract
Apart from the seven medical treatises excavated from Laoguanshan Tomb M3, there were also medical artifacts: an iron mortar and pestle for medicine, remains of plants that seem to be medicine, and a tiny figurine decorated with red and white lacquered lines. In accordance with the Han period funerary practice of “serving the dead as serving the living” (shi si ru shi sheng 事死如事生), these funerary medical artifacts are likely related to the profession and daily life of the tomb’s occupier, in this case, very probably a medical official. This article introduces the lacquer figurine and the “channels” (jingmai 經脈) it illustrates in relation to roughly contemporaneous textual accounts of similar channels that have been excavated from tombs that were sealed in the Western Han (202 BCE–9 CE) period, as well as to accounts in the medical classics that were passed down and printed over one thousand years later than the date of the Laoguanshan tomb.