bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas
Authors: Desai Pankaj B. , Karve Aniruddha S. , Zawit Misam , Arora Priyanka , Dave Nimita , Awosika Joy , Li Ningjing , Fuhrman Bethany , Medvedovic Mario , Sallans Larry , Kendler Ady , DasGupta Biplab , Plas David , Curry Richard , Zuccarello Mario , Chaudhary Rekha , Sengupta Soma , Wise-Draper Trisha M. 
Published: March 2024

Abstract

Purpose:
High-grade gliomas (HGG) carry a poor prognosis, with glioblastoma accounting for almost 50% of primary brain malignancies in the elderly. Unfortunately, despite the use of multiple treatment modalities, the prognosis remains poor in this population. Our preclinical studies suggest that the presence of aromatase expression, encoded by CYP19A1, is significantly upregulated in HGGs. Remarkably, we find that letrozole (LTZ), an FDA-approved aromatase inhibitor, has marked activity against HGGs.

Patients and Methods:
We conducted a phase 0/I single-center clinical trial (NCT03122197) to assess the tumoral availability, pharmacokinetics (PK), safety, and tolerability of LTZ in recurrent patients with HGG. Planned dose cohorts included 2.5, 5, 10, 12.5, 15, 17.5, and 20 mg of LTZ administered daily pre- and postsurgery or biopsy. Tumor samples were assayed for LTZ content and relevant biomarkers. The recommended phase 2 dose (R2PD) was determined as the dose that resulted in predicted steady-state tumoral extracellular fluid (ECF; Css,ecf) &gt;2 μmol/L and did not result in ≥33% dose-limiting adverse events (AE) assessed using CTCAE v5.0.

Results:
Twenty-one patients were enrolled. Common LTZ-related AEs included fatigue, nausea, musculoskeletal, anxiety, and dysphoric mood. No DLTs were observed. The 15 mg dose achieved a Css,ecf of 3.6 ± 0.59 μmol/L. LTZ caused dose-dependent inhibition of estradiol synthesis and modulated DNA damage pathways in tumor tissues as evident using RNA-sequencing analysis.

Conclusions:
On the basis of safety, brain tumoral PK, and mechanistic data, 15 mg daily is identified as the RP2D for future trials.
Long-term Multimodal Recording Reveals Epigenetic Adaptation Routes in Dormant Breast Cancer Cells
Authors: Rosano Dalia , Sofyali Emre , Dhiman Heena , Ghirardi Chiara , Ivanoiu Diana , Heide Timon , Vingiani Andrea , Bertolotti Alessia , Pruneri Giancarlo , Canale Eleonora , Dewhurst Hannah F. , Saha Debjani , Slaven Neil , Barozzi Iros , Li Tong , Zemlyanskiy Grigory , Phillips Henry , James Chela , Győrffy Balázs , Lynn Claire , Cresswell George D. , Rehman Farah , Noberini Roberta , Bonaldi Tiziana , Sottoriva Andrea , Magnani Luca 
Published: March 2024

Abstract

Patients with estrogen receptor–positive breast cancer receive adjuvant endocrine therapies (ET) that delay relapse by targeting clinically undetectable micrometastatic deposits. Yet, up to 50% of patients relapse even decades after surgery through unknown mechanisms likely involving dormancy. To investigate genetic and transcriptional changes underlying tumor awakening, we analyzed late relapse patients and longitudinally profiled a rare cohort treated with long-term neoadjuvant ETs until progression. Next, we developed an in vitro evolutionary study to record the adaptive strategies of individual lineages in unperturbed parallel experiments. Our data demonstrate that ETs induce nongenetic cell state transitions into dormancy in a stochastic subset of cells via epigenetic reprogramming. Single lineages with divergent phenotypes awaken unpredictably in the absence of recurrent genetic alterations. Targeting the dormant epigenome shows promising activity against adapting cancer cells. Overall, this study uncovers the contribution of epigenetic adaptation to the evolution of resistance to ETs.

Significance:
This study advances the understanding of therapy-induced dormancy with potential clinical implications for breast cancer. Estrogen receptor-positive breast cancer cells adapt to endocrine treatment by entering a dormant state characterized by strong heterochromatinization with no recurrent genetic changes. Targeting the epigenetic rewiring impairs the adaptation of cancer cells to ETs.
See related commentary by Llinas-Bertran et al., p. 704.
This article is featured in Selected Articles from This Issue, p. 695
Curating the Republic: The Origins of the US Embassy
Authors: Ponti Katrina 
Published: March 2024

Summary
What can the historical study of early American legations in Europe tell us about how the United States approaches its embassies in the world today? Embassy buildings today represent over two hundred years of American trial and error in constantly shifting foreign political environments. They are, by their nature, intended to straddle multiple modalities: public and private; political and personal; global and local. It was because of their deliberately fluid representational states that the first American diplomatic missions to Europe could attempt to bridge the paradigm of aristocratic and democratic approaches to embassy curation abroad. As the first modern post-colonial democracy, the diplomatic agents of the US experimented with the placement, decoration and occupation of their ministerial spaces. In doing so, they innovated strategies of fluidity still seen in American embassies today.
On some new and little-known Palaearctic species of the genus Leptochilus de Saussure, 1853 (Hymenoptera: Vespidae: Eumeninae)
Authors: FATERYGA ALEXANDER V. 
Published: March 2024

Two new species are described: Leptochilus (Euleptochilus) barkalovi Fateryga, sp. nov. from Turkmenistan and L. (Lionotulus) puzanovi Fateryga, sp. nov. from Dagestan Republic, Russia. Leptochilus barkalovi is closely related to L. (E.) limbiferus (Morawitz, 1867) from which differs, in the male sex, by narrower clypeus, blunter angles of pronotum, longer pilosity on head and mesosoma, and light-colored apical lamella of tergum 2, as well as a different structure of flagellomere 11 and aedeagus. Leptochilus puzanovi is apparently related to L. (Lionotulus) tarsatus (de Saussure, 1855) from which differs, in the female sex, by broader head, deeper emarginate apical margin of clypeus, broader mesosoma, and dark brown apical lamella of tergum 2. The hitherto unknown males of L. (Lionotulus) incertus (Kostylev, 1940) and L. (L.) leleji Fateryga, 2019 are described; the females are re-described. For the first time, L. incertus is reported from Mongolia and L. leleji from Tyva Republic, Russia. Leptochilus (Lionotulus) nacrocephalus (Kostylev, 1940), stat. nov. is raised to a full species, re-described, and reported for the first time from Armenia.
Classifying Microwave Radiometer Observations over the Netherlands into Dry, Shallow, and Nonshallow Precipitation Using a Random Forest Model
Authors: Bogerd Linda , Kidd Chris , Kummerow Christian , Leijnse Hidde , Overeem Aart , Petkovic Veljko , Whan Kirien , Uijlenhoet Remko 
Published: March 2024

Abstract
Spaceborne microwave radiometers represent an important component of the Global Precipitation Measurement (GPM) mission due to their frequent sampling of rain systems. Microwave radiometers measure microwave radiation (brightness temperatures Tb), which can be converted into precipitation estimates with appropriate assumptions. However, detecting shallow precipitation systems using spaceborne radiometers is challenging, especially over land, as their weak signals are hard to differentiate from those associated with dry conditions. This study uses a random forest (RF) model to classify microwave radiometer observations as dry, shallow, or nonshallow over the Netherlands—a region with varying surface conditions and frequent occurrence of shallow precipitation. The RF model is trained on five years of data (2016–20) and tested with two independent years (2015 and 2021). The observations are classified using ground-based weather radar echo top heights. Various RF models are assessed, such as using only GPM Microwave Imager (GMI) Tb values as input features or including spatially aligned ERA5 2-m temperature and freezing level reanalysis and/or Dual-Frequency Precipitation Radar (DPR) observations. Independent of the input features, the model performs best in summer and worst in winter. The model classifies observations from high-frequency channels (≥85 GHz) with lower Tb values as nonshallow, higher values as dry, and those in between as shallow. Misclassified footprints exhibit radiometric characteristics corresponding to their assigned class. Case studies reveal dry observations misclassified as shallow are associated with lower Tb values, likely resulting from the presence of ice particles in nonprecipitating clouds. Shallow footprints misclassified as dry are likely related to the absence of ice particles.

Significance Statement
Published research concerning rainfall retrieval algorithms from microwave radiometers is often focused on the accuracy of these algorithms. While shallow precipitation over land is often characterized as problematic in these studies, little progress has been made with these systems. In particular, precipitation formed by shallow clouds, where shallow refers to the clouds being close to Earth’s surface, is often missed. This study is focused on detecting shallow precipitation and its physical characteristics to further improve its detection from spaceborne sensors. As such, it contributes to understanding which shallow precipitation scenes are challenging to detect from microwave radiometers, suggesting possible ways for algorithm improvement.
Enhancing predictions with a stacking ensemble model for ICU mortality risk in patients with sepsis-associated encephalopathy
Authors: Liu Xuhui , Niu Hao , Peng Jiahua 
Published: March 2024

Objective We identified predictive factors and developed a novel machine learning (ML) model for predicting mortality risk in patients with sepsis-associated encephalopathy (SAE). Methods In this retrospective cohort study, data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) and eICU Collaborative Research Database were used for model development and external validation. The primary outcome was the in-hospital mortality rate among patients with SAE; the observed in-hospital mortality rate was 14.74% (MIMIC IV: 1112, eICU: 594). Using the least absolute shrinkage and selection operator (LASSO), we built nine ML models and a stacking ensemble model and determined the optimal model based on the area under the receiver operating characteristic curve (AUC). We used the Shapley additive explanations (SHAP) algorithm to determine the optimal model. Results The study included 9943 patients. LASSO identified 15 variables. The stacking ensemble model achieved the highest AUC on the test set (0.807) and 0.671 on external validation. SHAP analysis highlighted Glasgow Coma Scale (GCS) and age as key variables. The model ( https://sic1.shinyapps.io/SSAAEE/ ) can predict in-hospital mortality risk for patients with SAE. Conclusions We developed a stacked ensemble model with enhanced generalization capabilities using novel data to predict mortality risk in patients with SAE.
Muscae volitantes: A 19th-century precursor of visual snow syndrome?
Authors: Weatherall Mark W. 
Published: March 2024

Purpose Visual snow syndrome comprises a whole-field static-like visual disturbance, with increased awareness of entopic phenomena, an inability to suppress the ‘just seen’ and photophobia. Visual snow syndrome is often associated with other problems such as headache, tinnitus, and anxiety. The earliest reported case of a patient experiencing symptoms consistent with visual snow syndrome dates only to 1995. This paper seeks to find patterns of experience in the medical literature of the past that are reminiscent of visual snow syndrome, to challenge the view that it is in any sense a novel disorder. Descriptions of subjective visual sensations such as experienced by patients suffering from visual snow syndrome were sought in treatises, textbooks and other literature generated by leading figures in 19th-century ophthalmology, physiology and physics. Conclusion While retrospective diagnosis of modern illness categories in historical medical literature is an enterprise fraught with pitfalls, it is nonetheless possible to see patterns of experience in the 19th-century medical literature that are strongly reminiscent of visual snow syndrome.
A comparison of cemented femoral fixation via anterior versus posterior approach total hip arthroplasty: an analysis of 60,739 total hip arthroplasties
Authors: Hoskins Wayne , Corfield Sophie , Peng Yi , Graves Stephen E , Bingham Roger 
Published: March 2024

Background: Anterior approach total hip arthroplasty (THA) decreases the rate of dislocation but increases femoral-sided complications in the way of periprosthetic fractures and component loosening. A cemented prosthesis may reduce femoral-sided complications and improve the risk:benefit profile of anterior approach THA. Methods: Data from the Australian National Joint Replacement Registry were analysed for patients undergoing primary THA via the anterior or posterior approach using a cemented polished femoral stem from January 2015 to December 2021. The primary outcome measure was the cumulative percent revision (CPR) for all causes and CPR for femoral component loosening and fracture. The CPR for the primary outcome measures were compared between the anterior and posterior approach and adjusted for age, sex, ASA score, BMI and femoral head size. Results: The study included 60,739 THAs with cemented stems (10,742 anterior, 49,997 posterior). The rate of revision of the anterior versus the posterior approach did not significantly differ (HR 0.87 (95% CI, 0.74–1.03), p = 0.100). Anterior approach THA had a significantly higher rate of revision for femoral component loosening (HR 5.06 [95% CI, 3.08–8.30], p < 0.001); and a decreased rate of revision for infection (HR 0.59 [95% CI, 0.43–0.81], p = 0.001) and dislocation/instability (HR 0–3 months 0.48 [95% CI, 0.27–0.83], p = 0.008; HR >3 months 0.30 [95% CI, 0.15–0.61], p < 0.001). There was no difference in the rate of revision surgery for fracture between the 2 approaches (HR 1.01 [95% CI, 0.71–1.43]), p = 0.975). Conclusions: There is no significant difference in overall revision rates with cemented femoral fixation performed with an anterior or posterior approach. Cemented fixation performed with the anterior approach partly mitigates femoral complications with no difference in the revision rate for fracture but an increased rate of femoral component loosening.
The content of patients’ emotional expressions during follow-up consultations for chronic diseases
Authors: Yasmina Kebir , Valérie Saint-Dizier de Almeida 
Published: March 2024

Objectives In this article, we seek to extract the themes that patients share when they express negative emotions in the context of follow-up consultation of chronic illness. We are mainly interested in patients with chronic illnesses, as these pathologies have a significant emotional overload leading to a significant deterioration of the patient's quality of life. Methods Our corpus included audio recordings of 12 chronic disease follow-up consultations conducted by physicians practicing in neurology, nutrition, internal medicine and infectiology. The 12 patients participating suffer from various chronic diseases: Parkinson's, HIV, diabetes, etc. We performed thematic content analyses on the emotional sequences in order to extract the themes underlying these emotional expressions. Results The 10 themes we have extracted are related to physical aspects, psychological aspects, the healthcare system and/or the healthcare provider, prognostic elements, social life, family life, aspects of professional life, issues of daily life, treatments and finally, aspects related to objectives and disease progress. Discussion/conclusion Our results show that follow-up consultations for chronic illnesses are consultations during which patients express emotions for different purposes. These emotional expressions concern particular themes that are not found in other forms of medical consultations. We will compare these results in the discussion part of this article.
Sex differences in multiple sclerosis relapse presentation and outcome: a retrospective, monocentric study of 134 relapse events
Authors: Thränhardt Pauline , Veselaj Admirim , Friedli Christoph , Wagner Franca , Marti Stefanie , Diem Lara , Hammer Helly , Radojewski Piotr , Wiest Roland , Chan Andrew , Hoepner Robert , Salmen Anke 
Published: March 2024

Background: Reporting of sex-specific analyses in multiple sclerosis (MS) is sparse. Disability accrual results from relapses (relapse-associated worsening) and independent thereof (progression independent of relapses). Objectives: A population of MS patients during relapse treated per standard of care was analyzed for sex differences and short-term relapse outcome (3–6 months) as measured by Expanded Disability Status Scale (EDSS) change. Design: Single-center retrospective study. Methods: We analyzed 134 MS relapses between March 2016 and August 2020. All events required relapse treatment (steroids and/or plasma exchange). Demographic, disease, and paraclinical characteristics [cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI)] were displayed separated by sex. Multivariable linear regression was run to identify factors associated with short-term EDSS change. Results: Mean age at relapse was 38.4 years (95% confidence interval: 36.3–40.4) with a proportion of 71.6% women in our cohort. Smoking was more than twice as prevalent in men (65.8%) than women (32.3%). In- and after-relapse EDSSs were higher in men [men: 3.3 (2.8–3.9), women: 2.7 (2.4–3.0); men: 3.0 (1.3–3.6); women: 1.8 (1.5–2.1)] despite similar relapse intervention. Paraclinical parameters revealed no sex differences. Our primary model identified female sex, younger age, and higher EDSS at relapse to be associated with EDSS improvement. A higher immunoglobulin G (IgG) quotient (CSF/serum) was associated with poorer short-term outcome [mean days between first relapse treatment and last EDSS assessment 130.2 (79.3–181.0)]. Conclusion: Sex and gender differences are important in outcome analyses of MS relapses. Effective treatment regimens need to respect putative markers for a worse outcome to modify long-term prognosis such as clinical and demographic variables, complemented by intrathecal IgG synthesis. Prospective trials should be designed to address these differences and confirm our results.
Efficacy of a Digital Diabetes Logbook for People With Type 1, Type 2, and Gestational Diabetes: Results From a Multicenter, Open-Label, Parallel-Group, Randomized Controlled Trial
Authors: Ehrmann Dominic , Hermanns Norbert , Finke-Gröne Katharina , Roos Timm , Kober Johanna , Schäfer Vanessa , Krichbaum Michael , Haak Thomas , Ziegler Ralph , Heinemann Lutz , Rieger Cosima , Bingol Ezgi , Kulzer Bernhard , Silbermann Stephan 
Published: March 2024

Background: In a randomized controlled trial, the efficacy of a digital diabetes diary regarding a reduction of diabetes distress was evaluated. Methods: A randomized controlled trial with a 12-week follow-up was conducted in 41 study sites across Germany. Key eligibility criteria were a diagnosis of type 1, type 2, or gestational diabetes and regular self-monitoring of blood glucose. Participants were randomly assigned (2:1 ratio) to either use the digital diabetes logbook (mySugr PRO), or to the control group without app use. The primary outcome was the reduction in diabetes distress at the 12-week follow-up. All analyses were based on the intention-to-treat population with all randomized participants. The trial was registered at the German Register for Clinical Studies (DRKS00022923). Results: Between February 11, 2021, and June 24, 2022, 424 participants (50% female, 50% male) were included, with 282 being randomized to the intervention group (66.5%) and 142 to the control group (33.5%). A total of 397 participants completed the trial (drop-out rate: 6.4%). The median reduction in diabetes distress was 2.41 (interquartile range [IQR]: −2.50 to 8.11) in the intervention group and 1.25 (IQR: −5.00 to 7.50) in the control group. The model-based adjusted between-group difference was significant (−2.20, IQR: −4.02 to −0.38, P = .0182) favoring the intervention group. There were 27 adverse events, 17 (6.0%) in the intervention group, and 10 (7.0%) in the control group. Conclusions: The efficacy of the digital diabetes logbook was demonstrated regarding improvements in mental health in people with type 1, type 2, and gestational diabetes.
Problematic coffee use and associated factors among medical and health science students in Dilla University, Ethiopia
Authors: Kassaw Chalachew , Regasa Rediet , Negash Misrak , Alemwork Amare , Abebe Lulu , Yimer Solomon , Anbesaw Tamrat , Alemayehu Selamawit 
Published: March 2024

Objective: Coffee holds a cherished place in Ethiopian culture, its consumption among students raises concerns despite its perceived benefits for alertness and productivity. Moderate caffeine intake remains unproblematic, but exceeding 400 mg daily can trigger detrimental health effects such as fatigue, memory impairment, and even attention-deficit disorder. Research on problematic coffee use among young adults, specifically Ethiopian students, remains limited, hindering our understanding of its potential scope and impact. To address this knowledge gap, researchers at Dilla University, Ethiopia, undertook a comprehensive study in 2022, focusing on the university’s student population. This investigation holds significant potential to unveil the previously obscured landscape of excessive coffee consumption in this demographic and inform future research and potential interventions. Methodology: An institutional-based cross-sectional study design was conducted in August–July, 2022. To measure problematic coffee use, this study used the Diagnostic Statistical Manual five criteria for substance use disorder. Those who scored >2 out of 11 criteria were considered to have problematic coffee use. To measure a significant association between the outcome and independent variable, a multivariable logistic regression analysis at p < 0.05 and 95% confidence interval was employed. Result: This study included 414 respondents. More than half of the respondents, 347 (59.7%) were male. Out of all respondents, 182 (44.0%) had a boy/girlfriend. Nearly half of the respondents, 218 (52.7%) were orthodox, Christian religion followers. According to this study’s findings, 137 (33.1%) respondents were considered to have problematic coffee use. Multivariable logistic regression analysis showed that 5–10 years duration of coffee use (AOR = 4.62, 95% CI: 2.96–7.85; p = 0.001), start to use coffee before joining university (AOR = 2.977, 95% CI: 1.332–6.653; p = 0.008) and 6–9 cups of daily coffee use (AOR = 3.26, 95% CI: 2.14–5.89; p = 0.00) were associated with problematic coffee use. Conclusion: This study showed that one-third of the respondents had problematic coffee use. The starting point, duration, and amount of use had a strong association with problematic coffee use. Hence, focusing on addressing the mental health challenges associated with problematic/excessive coffee consumption among higher education students is advisable. Additionally, promoting awareness of problematic/excessive coffee use and its potential remedies is recommended.