bluuebunny/crossref_metadata_2025_split huggingface dataset:
The study of pubertal stage and age of menarche in girls in Isfahan province, Iran
Authors: Mozafarian Nafiseh , Hashemipour Mahin , Maracy Mohammad Reza , Pourrajab Masoumeh , Omidi Razieh , Kelishadi Roya 
Published: January 2025

Abstract

Background
The onset age of pubertal changes varies widely among girls and has undergone changes over time around the world. This study aimed to determine the age of onset of puberty in healthy Iranian girls living in Isfahan province.

Methods
This cross- sectional study was conducted among 13,886 students aged 6–18 years. They were selected by multistage random cluster sampling from urban and rural areas of Isfahan province of Iran. Pubertal stage was determined according the 5-level Tanner stages proposed by Marshall and Tanner. Trained physicians determined the breast development through both visual inspection and palpation, in addition, mothers assessed their daughter’s pubic hair growth using Tanner’s Sexual Maturation Scale (SMS) by comparison to standard pictures. The data were analyzed by the status quo method. Probit regression analysis was used to evaluate the median age of onset for each characteristic including menarche, breast and pubic hair.

Results
A total of 13,886 healthy girls with mean age (SD) of 11.97 (2.9) were studied. Overall 6968 (50.2%) girls experienced menstruation with a median (95%CI) age of 12.05(11.88–12.21) years at its onset. The median age for onset of breast development was 9.89 (95% CI: 9.77 − 10.02) years and for onset of pubic hair development was 10.14 (95% CI: 9.88– 10.39) years. The 3rd percentile for breast stage 2 (B2) and pubic hair stage 2 (PH2) was 6.85 and 6.75 years, respectively, and the 97th percentile for B2 and PH2 was 12.94and 13.54 years, respectively.

Conclusion
According to our findings, the onset of puberty before 6.85 years should be considered as precocious puberty for Iranian girls. Our study indicated the secular trend toward earlier menarche in girls. Nationally representative surveys and longitudinal studies are necessary to determine the exact age of puberty for future international comparisons.
Perceptions and experiences of healthcare professionals of implementing the Organ Donation (Deemed Consent) Act in England during the Covid-19 pandemic
Authors: Al-Haboubi Mustafa , McLaughlin Leah , Williams Lorraine , Noyes Jane , O’Neill Stephen , Boadu Paul , Bostock Jennifer , Mays Nicholas 
Published: January 2025

Abstract

Context
In May 2020 during the COVID-19 pandemic, England implemented a ‘soft’ opt-out system of consent to deceased organ donation. As part of a wider evaluation, this analysis focused on the perceptions of health care professionals, specifically their experiences of implementation.

Methods
Mixed-methods study informed by Normalisation Process Theory, based on two national surveys of health care professionals and interviews, observations and document analysis, across two case study sites. Routine NHS Blood and Transplant’s audit data provided context.

Findings
70 interviews with 59 staff and 244 first and 738 second surveys. COVID-19 affected every aspect of implementation. Although supportive in principle, many staff were unconvinced that legislative changes alone would increase consent rates. Many staff were redeployed or left their jobs. As a result, staff were not able to work collectively as intended for implementation. Staff received routine donor audit data suggesting the law was yet to make a difference to consent rates, reducing their enthusiasm and commitment.

Conclusions
Implementation could have been more impactful if delayed. The National Health Service needs to reprioritise organ donation and relaunch the implementation plan in the post-pandemic period, though it is unlikely the changes will bring about a significant increase in consent rates.
Assessing the determinants of out-of-pocket health expenditures among Cambodian households in informal employment using survey data
Authors: Kaiser Andrea Hannah , Mao Sovathiro , Sundewall Jesper , Ross Marlaina , Koy Sokunthea , Vorn Searivoth , Koeut Pichenda , Ekman Bjoern 
Published: January 2025

Abstract

Background
As the deadline for the Sustainable Development Goals approaches, financial protection in Cambodia remains inadequate, especially for nonpoor informal workers lacking formal social health protection coverage or access to other prepayment schemes. This exposes them to high out-of-pocket health expenditures (OOPE) and related financial hardship. To better understand the drivers behind these expenditures, our study aims to model their healthcare, health, and social determinants and to assess their relative importance.

Methods
In 2023, we conducted a cross-sectional multistage clustered sampling survey across seven Cambodian provinces, surveying 3,254 households engaged in informal employment and not covered by any formal social health protection scheme. The survey gathered information on households’ use of outpatient and inpatient care and associated OOPE. We employed generalized linear models (GLMs) to analyse the healthcare, health, and social determinants of OOPE and the OOPE budget share (the proportion of total annual household consumption expenditure spent on OOPE) and applied Shapley decomposition analysis to quantify the relative contributions of these determinants to the explained variance in our outcomes.

Results

Healthcare variables were the dominant contributors to the explained variance in all outcomes (41.36–50.73%), followed by health factors. While several social variables were significant, only the wealth quintile made notable contributions to explaining variance in our outcomes. The key healthcare contributors included the sector type and level of care, and the number of outpatient medications. Important health contributors included illness severity and the presence of chronic illnesses or noncommunicable diseases.

Conclusions
Our findings emphasize the necessity of integrating nonpoor informal workers and their dependents into formal prepayment schemes to reduce OOPE and enhance financial protection on Cambodia’s path toward universal health coverage. Strategically engaging with private providers and pharmacies to improve access to essential services and medicines, coupled with the implementation of an effective referral system are important policy considerations to this end. Further research is needed on how health determinants are modifiable with policy interventions. Our findings can assist the Cambodian government in advancing its universal health coverage goals and offer insights for other countries aiming to extend coverage to similar population groups.
Detection of breast cancer lesions using APT weighted MRI: a systematic review
Authors: Lee Ryan C. , Boparai Montek Singh , Duong Tim Q. 
Published: January 2025

Abstract
Amide proton transfer (APT) is a novel magnetic resonance imaging (MRI) technique that has shown promising ability to study cancers. This paper systematically reviewed the literature on the use of APT MRI in the prognosis of breast cancer. A literature search was conducted on Pubmed and Embase and a total of 14 articles comprising 775 patients were included in the review. APT MRI had the ability to distinguish between benign and malignant lesions with an AUC as high as 0.959. There is a positive correlation between APT signal intensity and tumor grade/stage as well as Ki-67, whereas no correlation was found with ER/PR/Her-2 receptor status. There was a greater decrease in APT signal intensity after neoadjuvant chemotherapy (NAC) in responders compared to non-responders, suggesting that APT MRI may serve as a valuable supplemental tool in the early identification of chemotherapy response. APT has the potential to complement with other imaging methods in the diagnosis, prognosis, treatment monitoring, and management of breast cancer. Additional studies and standardization of APT acquisition methods are needed.
Myeloid cell-derived apCAFs promote HNSCC progression by regulating proportion of CD4+ and CD8+ T cells
Authors: Ren Feilong , Meng Lin , Zheng Shize , Cui Jiasen , Song Shaoyi , Li Xing , Wang Dandan , Li Xing , Liu Qilin , Bu Wenhuan , Sun Hongchen 
Published: January 2025

Abstract
It is well-known that cancer-associated fibroblasts (CAFs) are involved in the desmoplastic responses in Head and Neck Squamous Cell Carcinoma (HNSCC). CAFs are pivotal in the tumor microenvironment (TME) molding, and exert a profound influence on tumor development. The origin and roles of CAFs, however, are still unclear in the HNSCC, especially antigen-presenting cancer-associated fibroblasts (apCAFs). Our current study tried to explore the origin, mechanism, and function of the apCAFs in the HNSCC. Data from single-cell transcriptomics elucidated the presence of apCAFs in the HNSCC. Leveraging cell trajectory and Cellchat analysis along with robust lineage-tracing assays revealed that apCAFs were primarily derived from myeloid cells. This transdifferentiation was propelled by the macrophage migration inhibitory factor (MIF), which was secreted by tumor cells and activated the JAK/STAT3 signaling pathway. Analysis of the TCGA database has revealed that markers of apCAFs were inversely correlated with survival rates in patients with HNSCC. In vivo experiments have demonstrated that apCAFs could facilitate tumor progression. Furthermore, apCAFs could modulate ratio of CD4+ T cells/CD8+ T cells, such as higher ratio of CD4+ T cells/CD8+ T cells could promote tumor progression. Most importantly, data from in vivo assays revealed that inhibitors of MIF and p-STAT3 could significantly inhibit the OSCC growth. Therefore, our findings show potential innovative therapeutic approaches for the HNSCC.

Significance: ApCAFs derived from myeloid cells promote the progression of HNSCC by increasing the ratio of CD4+/CD8+ cells, indicating potential novel targets to be used to treat the human HNSCC.

Graphical Abstract
Exosomal insights into ovarian cancer stem cells: revealing the molecular hubs
Authors: Sojoudi Kiana , Solaimani Maryam , Azizi Hossein 
Published: January 2025

Abstract
Ovarian cancer is a deadly disease, often diagnosed at advanced stages due to a lack of reliable biomarkers. Exosomes, which carry a variety of molecules such as proteins, lipids, DNA, and non-coding RNAs, have recently emerged as promising tools for early cancer detection. While exosomes have been studied in various cancer types, comprehensive network analyses of exosome proteins in ovarian cancer remain limited. In this study, we used a protein-protein interaction (PPI) network. Using the Clustermaker2 app and the MCODE algorithm, we identified six significant clusters within the network, highlighting regions involved in functional pathways. A four-fold algorithmic approach, including MCC, DMNC, Degree, and EPC, identified 12 common hub genes. STRING analysis and visualization techniques provided a detailed understanding of the biological processes associated with these hub genes. Notably, 91.7% of the identified hub genes were involved in translational processes, showing an important role in protein synthesis regulation in ovarian cancer. In addition, we identified the miRNAs and LncRNAs carried by ovarian cancer exosomes. These findings highlight potential biomarkers for early detection and therapeutic targets.
Nociceptor-localized KCC2 suppresses brachial plexus avulsion-induced neuropathic pain and related central sensitization
Authors: Xian Hang , Guo Huan , Liu Yuan-Ying , Ma Sui-Bin , Zhao Rui , Zhang Jian-Lei , Zhang Hang , Xie Rou-Gang , Guo Xu-Cheng , Ren Jie , Wu Sheng-Xi , Luo Ceng , Cong Rui 
Published: January 2025

Abstract
Lack in understanding of the mechanism on brachial plexus avulsion (BPA)-induced neuropathic pain (NP) is the key factor restricting its treatment. In the current investigation, we focused on the nociceptor-localized K+-Cl− cotransporter 2 (KCC2) to investigate its role in BPA-induced NP and related pain sensitization. A novel mice model of BPA on the middle trunk (C7) was established, and BPA mice showed a significant reduction in mechanical withdrawal threshold of the affected fore- and hind- paws without affecting the motor function through CatWalk Gait analysis. Decreased expression of KCC2 in dorsal root ganglion (DRG) was detected through Western blot and FISH technology after BPA. Overexpression of KCC2 in DRG could reverse the hyperexcitability of DRG neurons and alleviate the pain of BPA mice synchronously. Meanwhile, the calcium response signal of the affected SDH could be significantly reduced through above method using spinal cord fiber photometry. The synthesis and release of brain-derived neurotrophic factor (BDNF) was also proved reduction through overexpression of KCC2 in DRG, which indicates BDNF can also act as the downstream role in this pain state. As in human-derived tissues, we found decreased expression of KCC2 and increased expression of BDNF and TrκB in avulsed roots of BPA patients compared with normal human DRGs. Our results indicate that nociceptor-localized KCC2 can suppress BPA-induced NP, and peripheral sensitization can be regulated to reverse central sensitization by targeting KCC2 in DRG at the peripheral level through BDNF signaling. The consistent results in both humanity and rodents endow great potential to future transformation of clinical practice.
Effect of drought disturbance in a sclerophyll forest on the micromammal community in the Río Clarillo National Park, Metropolitan Region, Chile
Authors: Fletcher Susan , Sarmiento Carlos , Stotz Gisela C. , Quirici Verónica 
Published: January 2025

Abstract

Background
Micromammals play an important role in mediterranean ecosystems. The “megadrought” in the sclerophyll forest has caused a “browning” that implies, among other things, the reduction of canopy cover. The effects of forest browning on the taxonomic and functional diversity of micromammals were evaluated.

Methods
Forests with high and low disturbance degree were characterized based on the level of browning and canopy cover. To study the community of micromammals in these forests, the Capture-Mark-Recapture method was used with Sherman traps. Community indices such as Shannon–Wiener and Pielou were calculated. The Coefficient of Variation was used to study functional diversity for each trait separately. Multivariate measures FRic, FEve and FDiv were used to determine multidimensional diversity.

Results
We observed differences in species composition and in richness, diversity, and cover variables between forest types. However, micromammal communities were similar in taxonomic and functional diversity in highly and slightly disturbed forests.

Discussion
The micromammal community appears to show some resistance to forest changes due to disturbance, which could be related to their generalist diet and high dispersal capacity. The presence of the genus Rattus could entail a decrease in native rodent diversity and could have a greater effect than the disturbance of the forest due to drought. These results are an invitation to conduct long-term studies to better understand the potential vulnerability of the different micromammal species to disturbed sclerophyll forests affected by drought.
CFO: Calibration-Free Odds Bayesian Designs for Dose Finding in Clinical Trials
Authors: Fang Jialu , Zhang Ninghao , Wang Wenliang , Yin Guosheng 
Published: January 2025

PURPOSE

Calibration-free odds type (CFO-type) designs have been demonstrated to be robust, model-free, and practically useful, which have become the state-of-the-art approach for dose finding. However, a key challenge for implementing such designs is a lack of accessible tools. We develop a user-friendly
R
package and
Shiny
web-based software to facilitate easy implementation of CFO-type designs. Moreover, we incorporate randomization into the CFO framework.

METHODS

We created the
R
package CFO and leveraged
R Shiny
to build an interactive web application, CFO suite, for implementing CFO-type designs. We introduce the randomized CFO (rCFO) design by integrating the exploration-exploitation mechanism into the CFO framework.

RESULTS
The CFO package and CFO suite encompass various variants tailored to different clinical settings. Beyond the fundamental CFO design, these include the two-dimensional CFO (2dCFO) for drug-combination trials, accumulative CFO (aCFO) for accommodating all dose information, rCFO for integrating exploration-exploitation via randomization, time-to-event CFO (TITE-CFO), and fractional CFO (fCFO) for addressing late-onset toxicity. Using all information and addressing delayed toxicity outcomes, TITE-aCFO and fractional-aCFO are also included. The package provides functions for determining the subsequent cohort dose, selecting the maximum tolerated dose, and conducting simulations to evaluate performance, with results presented through textual and graphical outputs.

CONCLUSION

The CFO package and CFO suite provide comprehensive and flexible tools for implementing CFO-type designs in phase I clinical trials. This work is highly significant as it integrates all existing CFO-type designs to facilitate novel trial designs with enhanced performance. In addition, this promotes the spread of statistical methods using a user-friendly
R
package and
Shiny
software. It strengthens collaborations between biostatisticians and clinicians, further enhancing trial performance in terms of efficiency and accuracy.
Nivolumab With or Without Ipilimumab in Patients With Recurrent or Metastatic Merkel Cell Carcinoma: A Nonrandomized, Open-Label, International, Multicenter Phase I/II Study
Authors: Bhatia Shailender , Topalian Suzanne L. , Sharfman William , Meyer Tim , Steven Neil , Lao Christopher D. , Fariñas-Madrid Lorena , Devriese Lot A. , Moore Kathleen , Ferris Robert L. , Honma Yoshitaka , Elias Ileana , Srirangam Anjaiah , Garnett-Benson Charlie , Lee Michelle , Nghiem Paul 
Published: January 2025

PURPOSE

Approximately 50% of patients with advanced Merkel cell carcinoma (MCC) have primary or acquired resistance to PD-(L)1 blockade, which may be overcome using combination immune checkpoint inhibition (ICI) with anti–cytotoxic T lymphocyte antigen-4 antibody. We present results from the recurrent/metastatic MCC cohort in CheckMate 358, a nonrandomized, multicohort, phase I/II study of nivolumab (NIVO) with or without ipilimumab (IPI) in virus-associated cancers (ClinicalTrials.gov identifier:
NCT02488759
).

METHODS
ICI-naïve patients with recurrent/metastatic MCC and 0-2 previous systemic therapies were administered NIVO monotherapy at 240 mg once every 2 weeks or combination therapy with NIVO 3 mg/kg once every 2 weeks + IPI 1 mg/kg once every 6 weeks. The primary end point was objective response. Secondary end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

RESULTS
Sixty-eight patients received NIVO (n = 25) or NIVO + IPI (n = 43). The objective response rate (95% CI) and median DOR (95% CI), respectively, were 60% (38.7 to 78.9) and 60.6 months (16.7 to not applicable [NA]) with NIVO and 58% (42.1 to 73) and 25.9 months (10.4 to NA) with NIVO + IPI. The median PFS (95% CI) and OS (95% CI), respectively, were 21.3 (9.2 to 62.5) and 80.7 (23.3 to NA) months with NIVO and 8.4 (3.7 to 24.3) and 29.8 (8.5 to 48.3) months with NIVO + IPI. The incidence of grade 3/4 treatment-related adverse events was 28% with NIVO and 47% with the combination.

CONCLUSION
This nonrandomized study showed frequent and durable responses with both NIVO and NIVO + IPI in patients with ICI-naïve advanced MCC. However, it did not show improvement in efficacy with the combination, thus contradicting previous study reports that had suggested clinical benefit with combination ICI. A randomized trial of NIVO + IPI versus NIVO monotherapy is warranted.
Predictive Performance of 2 Immunoassays in Patients with Graves Disease Undergoing Radioiodine Therapy: Prospective Study
Authors: de Souza Marcus Vinícius Rodrigues , Sapienza Marcelo Tatit , Brito Luciana Pinto , Cortez Pedro Afonso , Marui Suemi 
Published: January 2025

Abstract

Context
Radioactive iodine (RAI) treatment is a well-established successful treatment for Graves disease (GD) but causes an increment in autoantibodies, particularly TSH receptor antibodies.

Objective
To assess the performance and prognostic role of Immulite thyroid-stimulating immunoglobulin (TSI) and Elecsys thyrotropin receptor antibodies (TRAbs) immunoassays in patients with GD undergoing RAI therapy.

Methods
Clinical and laboratory data of 188 patients (156 GD and 32 toxic nodule goiter), undergoing RAI therapy between January 2018 and January 2022 were prospectively collected over 12 months. Refractoriness was defined as persistent or recurrent hyperthyroidism 6 months post-RAI treatment without levothyroxine. Statistical analysis included descriptive statistics, logistic regression, and generalized estimated equations.

Results
Patients had a mean age of 46.4 years, and 78.2% were women. RAI therapy was indicated in 94.2% due to uncontrolled hyperthyroidism or ATD therapy relapse (median of 35 months). Immulite TSI showed higher clinical sensitivity and accuracy (area under the curve [AUC]: 0.98, sensitivity 92.0%, accuracy 98.4%) than Elecsys TRAb (AUC: 0.97, sensitivity 82.1%, accuracy 91.2%). Successful treatment was achieved in 112 of 126 GD patients (89%). Thyroid volume, 2-hour iodine-131 uptake, free thyroxine and thyroxine levels, Elecsys TRAb, and Immulite TSI were significantly higher in the refractory group (P &lt; 0.05), despite most patients receiving &gt;300 Gy of RAI. Longitudinal thyrotropin evaluation predicted treatment response at 12 months (P = .01), whereas autoantibodies did not.

Conclusion
Refractoriness to RAI therapy was associated with higher levels of Immulite TSI and Elecsys TRAb prior to treatment. Although AUCs for both assays were equivalent, Immulite TSI demonstrated superior clinical sensitivity and accuracy. Despite distinct autoantibody patterns emerging post-RAI, longitudinal monitoring did not predict treatment response after 1 year but indicated persistently high concentrations.
Χώροι τέχνης και αστική πολιτική: Η ενσωμάτωση των καλλιτεχνικών χώρων στις διαδικασίες του αστικού εξευγενισμού
Authors: Μπολωνάκη Στυλιανή 
Published: January 2025

Το άρθρο εστιάζεται στους νέους χώρους τέχνης στην Αθήνα, οι οποίοι κάτω από τον όρο «δημιουργικές πρωτοβουλίες» έχουν εξελιχθεί σε βασικούς παράγοντες της aθηναϊκής αστικής αναγέννησης, συστήνοντας τη δημιουργικότητα ως μοχλό κοινωνικοοικονομικής ανάπτυξης των aθηναϊκών συνοικιών. Το κείμενο επεξεργάζεται τα χαρακτηριστικά των χώρων αυτών, αναλύοντας τη γενεαλογία τους και τη δυναμική τους ενσωμάτωση στην παραγωγή της πόλης, εστιάζοντας στα παραδείγματα των ευρωπαϊκών πόλεων και δίνοντας ιδιαίτερη έμφαση στο μοντέλο που εφαρμόζεται στο Παρίσι σήμερα, αντλώντας από δύο γνωσιολογικά πεδία: τις αστικές σπουδές και την κοινωνιολογία της τέχνης. Το άρθρο επιθυμεί να προσφέρει μια νέα οπτική στους διαύλους επικοινωνίας μεταξύ της καλλιτεχνικής πρακτικής και της αστικής πολιτικής.