bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Target‐Mediated Disposition on Iptacopan Clinical Pharmacokinetics in Participants with Normal or Impaired Hepatic Function
Authors: Burmeister Getz Elise , Stein Richard R. , Fink Martin , Kulmatycki Kenneth , Baltcheva Irina , Weis Wendy , Shah Bharti , Lawitz Eric , Schmouder Robert
Published: January 2025

Iptacopan, a first‐in‐class complement factor B inhibitor acting proximally in the alternative complement pathway, has been shown to be safe and effective for patients with complement‐mediated diseases. Iptacopan selectively binds with high affinity to factor B, a soluble, plasma‐based, hepatically produced protein. Factor B is abundant in the circulation but can be saturated at the iptacopan clinical dose of 200 mg twice daily. Iptacopan pharmacokinetics (PK) are influenced by target binding. This target‐mediated drug disposition (TMDD) behavior makes PK data useful for understanding target occupancy and motivates modeling of drug‐target binding to connect exposure with pharmacological effect. A phase I hepatic impairment (HI) PK study measuring both total and unbound iptacopan PK profiles provided an opportunity to characterize the effect of variation in target concentration (due to varying hepatic function) on iptacopan PK. HI caused no change in total iptacopan exposure but increased unbound iptacopan exposure 1.38‐ to 3.72‐fold in participants with mild, moderate, or severe HI relative to demographically matched participants with normal hepatic function, with the largest increases in severe HI. A two‐site competitive binding model was developed to elucidate the relationship between iptacopan PK and factor B occupancy to characterize exposure thresholds for maximal target engagement. The model was used to assess alternative dose regimens to provide insight into how to approach dose recommendations for patients with severe HI. This study provides an example of small‐molecule TMDD, a behavior typically associated with targeted biologics; its importance is too often underappreciated in small‐molecule drug development.
Palbociclib Is Safe for Breast Cancer Patients With Mild Hepatic Impairment: A Multicenter Retrospective Study Using Real‐World Data
Authors: Bos Alieke K. , Willemsen Annelieke E.C.A.B. , Visser Loes E. , Stoker Lennart J. , Kingma Jurjen S. , Rommers Mirjam K. , Kuck Emile M. , van der Linden Paul D. , van Nuland Merel
Published: January 2025

The liver is crucial for metabolizing the anticancer drug palbociclib, but limited information is available on the impact of hepatic impairment on its toxicity and efficacy, with no real‐world data available. This study aims to evaluate how hepatic impairment affects hematological toxicity and progression‐free survival (PFS) of palbociclib in advanced hormone receptor‐positive/human epidermal growth factor receptor 2‐negative breast cancer, using the National Cancer Institute scoring system, in a large real‐world dataset. This multicenter retrospective observational study included female patients treated with palbociclib between August 2017 and February 2024. Regression analysis was used to compare the risk of developing grade 3/4 hematological toxicity and PFS between patients with normal and mild impaired liver function. In total, 478 female patients were included. Patients with mild hepatic impairment (n = 205) did not have an increased risk of developing grade 3/4 neutropenia compared with patients with normal hepatic function (n = 273) (hazard ratio (HR) = 1.11; 95% CI 0.83–1.47). In addition, the PFS was not significantly different between both groups (HR = 1.15; 95% CI 0.93–1.42). In real‐world settings, patients with mild hepatic impairment do not have a higher risk of developing palbociclib‐induced neutropenia or disease progression than patients with normal hepatic function. These findings can guide clinicians when treating breast cancer patients with mild hepatic impairment.
Effect of Bacille Calmette–Guérin vaccination on immune responses to SARS‐CoV‐2 and COVID‐19 vaccination
Authors: Messina Nicole L , Germano Susie , Chung Amy W , van de Sandt Carolien E , Stevens Natalie E , Allen Lilith F , Bonnici Rhian , Croda Julio , Counoupas Claudio , Grubor‐Bauk Branka , Haycroft Ebene R , Kedzierska Katherine , McDonald Ellie , McElroy Rebecca , Netea Mihai G , Novakovic Boris , Perrett Kirsten P , Pittet Laure F , Purcell Ruth A , Subbarao Kanta , Triccas James A , Lynn David J , Curtis Nigel ,   the BRACE Trial Consortium Group
Published: January 2025

Objectives

Bacille Calmette–Guérin (BCG) vaccination has off‐target effects on disease risk for unrelated infections and immune responses to vaccines. This study aimed to determine the immunomodulatory effects of BCG vaccination on immune responses to vaccines against SARS‐CoV‐2.

Methods

Blood samples, from a subset of 275 SARS‐CoV‐2‐naïve healthcare workers randomised to BCG vaccination (BCG group) or no BCG vaccination (Control group) in the BRACE trial, were collected before and 28 days after the primary course (two doses) of ChAdOx1‐S (Oxford‐AstraZeneca) or BNT162b2 (Pfizer‐BioNTech) vaccination. SARS‐CoV‐2‐specific antibodies were measured using ELISA and multiplex bead array, whole blood cytokine responses to γ‐irradiated SARS‐CoV‐2 (iSARS) stimulation were measured by multiplex bead array, and SARS‐CoV‐2‐specific T‐cell responses were measured by activation‐induced marker and intracellular cytokine staining assays.

Results

After randomisation (mean 11 months) but prior to COVID‐19 vaccination, the BCG group had lower cytokine responses to iSARS stimulation than the Control group. After two doses of ChAdOx1‐S, differences in iSARS‐induced cytokine responses between the BCG group and Control group were found for three cytokines (CTACK, TRAIL and VEGF). No differences were found between the groups after BNT162b2 vaccination. There were also no differences between the BCG and Control groups in COVID‐19 vaccine‐induced antigen‐specific antibody responses, T‐cell activation or T‐cell cytokine production.

Conclusion

BCG vaccination induced a broad and persistent reduction in ex vivo cytokine responses to SARS‐CoV‐2. Following COVID‐19 vaccination, this effect was abrogated, and BCG vaccination did not influence adaptive immune responses to COVID‐19 vaccine antigens.
Engineering the future of medicine: Natural products, synthetic biology and artificial intelligence for next‐generation therapeutics
Authors: Bülbül Emre F. , Bode Helge B. , Schmitt Steven , Bozhüyük Kenan A. J.
Published: January 2025

The eXchange Unit between Thiolation domains approach and artificial intelligence (AI)‐driven tools like Synthetic Intelligence are transforming nonribosomal peptide synthetase and polyketide synthase engineering, enabling the creation of novel bioactive compounds that address critical challenges like antibiotic resistance and cancer. These innovations expand chemical space and optimize biosynthetic pathways, offering precise and scalable therapeutic solutions. Collaboration across synthetic biology, AI, and clinical research is essential to translating these breakthroughs into next‐generation treatments and revolutionizing drug discovery and patient care.
Decoding Circular Dichroism Contributions in Chiral Hybrid Perovskites
Authors: Alehyane Amina , Fortino Mariagrazia , Barbault Florent , Monari Antonio , Pietropaolo Adriana
Published: January 2025

Hybrid organic–inorganic perovskites (HOIPs) are promising materials in optoelectronics, particularly for photovoltaic applications, due to their tunable properties and ease of fabrication. Among them, chiral HOIPs are gaining attention for their unique chiroptical properties, by the incorporation of chiral organic molecules into their structure. Despite their potential, the relationship between chiral HOIP structures and their chiroptical properties, such as circular dichroism (CD) spectra, remains challenging to decrypt. This study introduces a simulation workflow based on Density Functional Theory (DFT) and Time‐Dependent DFT (TD‐DFT) to model the CD spectrum of the chiral 2D perovskite encapsulating S‐1‐(3‐bromophenyl)‐ethylamine (S‐(3Br‐MBA)₂PbI₄). The approach combines ab‐initio molecular dynamics (AIMD) with TD‐DFT calculations evaluating the contributions on the whole chiral hybrid perovskite scaffold and those of the isolated ligands, allowing us to dissect the contributions to the CD spectrum of chiral ligands and of the metal‐halide sublattice. Additionally, the absorption dissymmetry factor gabs has been also computed finding good agreement with the experimental value.

This work provides valuable insights for the design of advanced chiroptoelectronic materials.
Base‐Promoted Tandem Synthesis of 6‐H‐Phenanthridine and its Derivatives
Authors: Jin Haoyu , Zeng Min , Wang Shouliang , Ding Yitian , Chen Suyang , Feng Jinxi , Chen Xianhao , Miao Tingting , Wu Fen , Shi Qian
Published: January 2025

Herein, we proposed a simple approach for synthesizing 6‐H‐phenanthridine through, which was a tandem reaction and promoted by base. 2′‐Fluoro‐[1,1′‐biphenyl]‐2‐carbaldehydes and LiN(SiMe3)2 were simply added and combined to obtain different structures of 6‐H‐phenanthridines (26 examples, ≤90 % yield). In the syntheses of 6‐H‐phenaridine, the transition metal‐free approach outlined in this paper is direct, convenient and easy to execute.
C−C Coupling of Ketones with Ethanol and Methanol Enabled by Nickel Catalysis
Authors: Sk Motahar , Ghosh Adrija , Mohan Kabadwal Lalit , Banerjee Debasis
Published: January 2025

Herein, we have reported the application of C1 and C2 alcohols for the C−C coupling with ketones enabled by nickel. De‐hydrogenation of ethanol took place under relatively milder conditions (100 °C) and resulted the functionalized 1,5‐diketones with acetophenone derivatives in one pot operation. Further, multi‐component strategy using ketones, and methanol in combination with various nitrogen‐based nucleophiles resulted the α‐aminomethylation under nickel‐catalysis. For a synthetic application, a series of tetra‐substituted pyridines have been demonstrated. Preliminary mechanistic investigations, control experiments and deuterium labelling studies were established the interrupted borrowing hydrogen (I‐BH) strategy. The catalytic transformations are highly sustainable and released water and dihydrogen as by products.
A cross‐sectional study comparing passive and eccentric modes of an isokinetic dynamometer to assess eccentric torque in trained athletes: Methodological considerations
Authors: Delextrat Anne , Sastre‐Munar Andreu , de Ste Croix Mark , Walsh Gregory
Published: January 2025

Some technical limitations to using the eccentric mode to measure peak eccentric strength of the hamstrings (PTHecc) were raised. PTHecc also has limited validity to predict performance or injury risk factor. Therefore, our aim was to compare PTHecc and other isokinetic variables tested in the eccentric and passive modes. Twenty male hockey players (20.2 ± 1.1 years; 179.7 ± 6.9 cm; 73.4 ± 7.1 kg and 12.2 ± 3.4% of body fat) performed maximal eccentric contractions of the hamstrings at 60°·s−1 (three repetitions) and 180°·s−1 (five repetitions) on both legs and using the eccentric mode and the passive mode (automatic movement of the lever arm) of the Biodex System 4 isokinetic dynamometer. The following variables were measured: PTHecc, the angle of peak torque (APT,°), angle‐specific Hecc torque at intervals of 10° and the rate of torque development (RTD) in the first 50 ms and the first 100 ms. The main results showed that compared to the eccentric mode, the passive mode led to a significantly greater PTHecc in the non‐dominant leg only and significantly smaller APT, RTD and angle‐specific Hecc at angles close to knee flexion. In contrast, significantly greater angle‐specific Hecc was observed in the passive mode at angles close to extension (10°–40°). This suggests that, although eccentric or concentric modes can be used to compare isokinetic data to existing literature, it is preferable to use the passive mode to assess peak torque or torque close to knee extension. The eccentric mode might be better to assess variables at the start of movement such as RTD.
An Integrated Heat Recovery System Design for a Fuel Cell Buggy With Hydrogen Preheating and Thermoelectric Generator
Authors: Hamdan M. H. , Mohamed W. A. N. W. , Aminudin M. A. , Kamarudin S. K. , Zakaria I. A. , Singh B.
Published: January 2025

This study presents an integrated heat recovery‐proton exchange membrane (IHR‐PEM) fuel cell system designed for lightweight vehicles powered by a 2 kW PEM fuel cell. The IHR system captures waste heat through multiple heat exchangers and integrates thermoelectric generator (TEG) modules for electrical regeneration and hydrogen preheating, enhancing PEM fuel cell performance. Utilizing the temperature gradient between the fuel cell's exhaust and the ambient environment, the system effectively converts waste heat into electrical energy, improving energy efficiency. Experimental evaluation under various operating parameters, including cruising speeds, PEM fuel cell loads, rejuvenation conditions, and electrical regeneration strategies, demonstrated the system's effectiveness. Results revealed waste heat absorption of up to 8.5 W and hydrogen preheating by 19°C, leading to an 11.5% increase in electrical power production and a maximum PEM fuel cell efficiency improvement of 11%. This study advances waste heat recovery (WHR) technologies in fuel cell‐based transportation, significantly improving energy efficiency and reducing carbon emissions. The findings provide valuable insights into the integration of regenerative WHR systems for lightweight vehicles, fostering the development of sustainable and energy‐efficient transportation solutions.
Gene−Air Pollution Interaction and Diversity of Genetic Sampling: The Southern California Children's Health Study
Authors: Po Justine , Morrison John , Marian Brittney , Chen Zhanghua , James Gauderman W. , Garcia Erika
Published: January 2025

Gene−environment interactions have been observed for childhood asthma, however few have been assessed in ethnically diverse populations. Thus, we examined how polygenic risk score (PRS) modifies the association between ambient air pollution exposure (nitrogen dioxide [NO2], ozone, particulate matter < 2.5 and < 10 μm) and childhood asthma incidence in a diverse cohort. Participants (n = 1794) were drawn from the Southern California Children's Health Study, a multi‐wave prospective cohort followed from 4th to 12th grade. PRS was developed using single nucleotide polymorphisms previously associated with childhood asthma. PRS−asthma associations and PRS−air pollutant interactions were estimated using Poisson regression. An interquartile range PRS increase was associated with 36% (95% CI: 9%, 70%) higher asthma incidence among non‐Hispanic children, but not associated with asthma among Hispanic children (rate ratio: 0.81 [95% CI: 0.62, 1.04]). NO2−PRS interaction was borderline significant in the overall sample (coefficient: 0.23 [95% CI: −0.03, 0.49]). Limited evidence was observed for a positive interaction between PRS and NO2 exposure associated with asthma incidence; however, the literature‐based PRS was not associated with asthma among Hispanic participants. Equitable, diverse genetic sampling approaches are needed to better identify clinically relevant SNPs in this population.
Response Surface Optimisation of Carbon Dioxide Adsorption Onto Palm Shell Activated Carbon Functionalised With Natural Amino Acids
Authors: Mohamed Hatta Nur Syahirah , Hussin Farihahusnah , Gew Lai Ti , Aroua Mohamed Kheireddine
Published: January 2025

Amino acids have shown promising results for carbon dioxide (CO2) capture when functionalised on solid materials; however, the functionalisation often relies on commercial synthetic amino acids. This study investigated the optimal CO2 adsorption performance of amino acid–functionalised material synthesised from palm shell–based activated carbon and natural amino acids, specifically egg white (EW) solution, in a continuous adsorption column. The process conditions of the column were optimised using response surface methodology. Four parameters, namely, the gas flow rate, adsorption temperature, CO2 concentration and EW concentration in the impregnation solution, were identified as significantly affecting CO2 adsorption performance. Good agreements were obtained between the predicted and experimental data, with the coefficients of determination ranging from 0.9639 to 0.9784. A maximum CO2 adsorption capacity of 1.1793 mmol/g was achieved under optimal process conditions: a gas flow rate of 200 mL/min, an adsorption temperature of 25°C, a CO2 concentration of 25 vol.%, and an EW concentration of 15 wt.%. The validation results further confirmed the reliability of the developed model equation in predicting the maximum CO2 adsorption capacity at a fixed 15 vol.% CO2 concentration, with low estimation error. The comparable results obtained using EW waste in this study represent a significant finding in the potential for waste valorisation, aligning with Sustainable Development Goal (SDG) 12 of the United Nations Sustainable Development Goals, as well as contributing to climate action as outlined in SDG 13.
Surgical Approaches to Pre‐Auricular Cutaneous Squamous Cell Carcinomas Extending to the Temporal Bone
Authors: Schachtel Michael , Gandhi Mitesh , Bowman James , Midwinter Mark , Panizza Benedict
Published: January 2025

Background

Standardized surgical approaches to advanced pre‐auricular cutaneous squamous cell carcinomas (cSCC) are lacking.

Methods

Fifty–four patients who underwent lateral temporal bone resection (LTBR) for pre‐auricular cSCC were grouped into “Levels” of increasing disease spread. Surgical approaches to achieve negative‐margin resection were designed for each Level and replicated on cadaveric specimens.

Results

Level 1 extended to the external auditory canal, requiring LTBR ± superficial parotidectomy. Level 2 involved the retromandibular space ± temporomandibular joint, necessitating partial mandibulectomy, in addition to the above. Level 3 and 4 involved the deep parotid, being situated either away from (> 5 mm) or close (≤ 5 mm) to the anterior carotid sheath (ACS), respectively. These tumors require radical parotidectomy, with incorporation of the ACS for Level 4. Level 5 involved the ACS at the skull base and should be treated non‐surgically.

Conclusion

This Level‐based system will hopefully lead to further prospective studies and improvements in outcomes for advanced pre‐auricular cSCC.
Oncogenic Human Papillomaviruses Drive One‐Third of Sinonasal Squamous Cell Carcinoma and Are Not Mutually Exclusive for Gene Mutations
Authors: Henrion Maxime , Costes‐Martineau Valérie , Bravo Ignacio González , Boulle Nathalie , Solassol Jérôme , Vendrell Julie , Garrel Renaud , Trinquet Aude , Lacheretz‐Szablewski Vanessa
Published: January 2025

Background

The detection rate of oncogenic human papillomaviruses (HPVs) in sinonasal squamous cell carcinomas (SNSCCs) varies among studies. The mutational landscape of SNSCCs remains poorly investigated.

Methods

We investigated the prevalence and prognostic significance of HPV infections based on p16 protein expression, HPV‐DNA detection, and E6/E7 mRNA expression using immunohistochemistry, polymerase chain reaction, and in situ hybridization, respectively. In addition, we evaluated the genetic mutations in 59 patients using next‐generation sequencing.

Results

One‐third of the SNSCCs were truly oncogenic HPV‐driven tumors associated with a nonkeratinizing morphology (p = 0.01) and did not correlate with the prognosis. The following gene mutations were detected: TP53, PIK3CA, CDKN2A, EGFR, and FGFR3. These mutations occurred alone, in association with, or with oncogenic HPV.

Conclusion

One‐third of SNSCCs were high‐risk HPV driven lesions. However, gene mutations and HR‐HPV infections are not mutually exclusive. Further studies are required to analyze the prognostic value of these associations.
Navigating the complexities of managing placenta accreta spectrum: A case series and literature review
Authors: Nyagaka Felix , Mutiso Steve , Oindi Felix
Published: January 2025

Placenta accreta spectrum (PAS) poses a significant risk for maternal morbidity and mortality. There is a global rise in incidence of PAS in tandem with an increase in rates of cesarian section. Previous cesarian section and presence of placenta previa are two independent risk factors for development of PAS. Other risk factors are dilatation and curettage, endometrial ablation, and hysteroscopy. Ultrasound and magnetic resonance imaging are useful in prenatal diagnosis, antenatal follow‐up, and pre‐operative planning. Patient care is individualized to optimize outcomes with appropriate preoperative counseling. However, a significant number of cases remain undiagnosed and are incidentally discovered during cesarian section or management for retained placenta. Patients may suffer significant morbidity such as postpartum hemorrhage, massive blood transfusion, injury to pelvic viscera, hysterectomy, acute kidney infection, and even death. Cesarean hysterectomy is the mainstay of treatment. In selected cases, conservative management may be offered. This includes leaving the placenta in situ with interval resolution, manual removal, application of compression sutures and balloon tamponade, myometrial resection with repair, and the triple P procedure. In this series, we present seven patients with PAS managed at a tertiary teaching and referral hospital in Kenya. We highlight and discuss their antenatal presentation, intraoperative findings, management and the postoperative course. Early diagnosis, involvement of multidisciplinary team, and good preoperative planning are key to achieving a good outcome. Patients with PAS should be managed in facilities with sufficient resources, skilled personnel to manage complications arising from treatment such as need for massive transfusion, and intensive care.
Benchmarking YOLO Variants for Enhanced Blood Cell Detection
Authors: Mehta Pooja , Vaghela Rohan , Pansuriya Nensi , Sarda Jigar , Bhatt Nirav , Bhoi Akash Kumar , Srinivasu Parvathaneni Naga
Published: January 2025

Blood cell detection provides a significant amount of information about a person's health, aiding in the diagnosis and monitoring of various medical conditions. Red blood cells (RBCs) carry oxygen, white blood cells (WBCs) play a role in immune defence, and platelets contribute to blood clotting. Changes in the composition of these cells can signal various physiological and pathological conditions, which makes accurate blood cell detection essential for effective medical diagnosis. In this study, we apply convolutional neural networks (CNNs), a subset of deep learning (DL) techniques, to automate blood cell detection. Specifically, we compare the performance of multiple variants of the You Only Look Once (YOLO) model, including YOLO v5, YOLO v7, YOLO v8 (in medium, small and nano configurations), YOLO v9c and YOLO v10 (in medium, small and nano configurations), for the task of detecting RBCs, WBCs and platelets. The results show that YOLO v5 achieved the highest mean average precision (mAP50) of 93.5%, with YOLO v10 variants also performing competitively. YOLO v10m achieved the highest precision for RBC detection at 85.1%, while YOLO v10n achieved 98.6% precision for WBC detection. YOLO v5 demonstrated the highest precision for platelets at 88.8%. Overall, YOLO models provided high accuracy and precision in detecting blood cells, making them suitable for medical image analysis. In conclusion, the study demonstrates that the YOLO model family, especially YOLO v5, holds significant potential for advancing automated blood cell detection. These findings can help improve diagnostic accuracy and contribute to more efficient clinical workflows.
The up‐regulation of RIPK3 mediated by ac4C modification promotes oxidative stress‐induced granulosa cell senescence by inhibiting the Nrf2/HO‐1 pathway
Authors: Zhang Wanjun , Zhang Jiahao , Zhang Yile , Zhai Jun , Sun Bo , Guo Yihong , Wang Fang
Published: January 2025

Abnormality of granulosa cells (GCs) is the critical cause of follicular atresia in premature ovarian failure (POF). RIPK3 is highly expressed in GCs derived from atretic follicles. We focus on uncovering how RIPK3 contributes to ovarian GC senescence. Primary GCs were treated with H₂O₂ to induce senescence. ROS was detected via DCFH‐DA staining. Levels of senescence‐related molecules and SA‐β‐Gal activity were examined. Cyclophosphamide was administered to mice to induce POF. The impact of RIPK3 on atretic follicles and sex hormones was evaluated through HE staining and ELISA, respectively. The acRIP‐qPCR analysis of RIPK3 ac4C levels, RIP detection for interaction between RIPK3 and NAT10, and actinomycin D treatment to detect RIPK3 degradation were conducted. In H2O2‐treated GCs and POF mouse ovaries, levels of RIPK3, ROS, senescence‐related molecules, as well as SA‐β‐Gal activity, were all up‐regulated, and this effect was suppressed by RIPK3 inhibition. RIPK3 interference reduced atretic follicles and FSH levels while increasing AMH and E2 levels. Nrf2 and HO‐1 content were diminished in the models, whereas si‐RIPK3 facilitated their expression. The effect of si‐RIPK3 on decreased levels of ROS and senescence‐related molecules was reversed by ML385. H2O2 decreased RIPK3 mRNA degradation and increased its ac4C modification. The ac4C modifying enzyme NAT10 was up‐regulated in the models, and NAT10 enhanced RIPK3 mRNA stability through ac4C modification. NAT10 knockdown mitigated ovarian GC senescence by inhibiting RIPK3 expression. The promotion of RIPK3 mRNA stability through ac4C modification by NAT10, in turn, affects the Nrf2/HO‐1 pathway and promotes ovarian GC senescence.
Sleep Duration and Quality in Adolescents: Associations With Suicidal Ideation
Authors: Lemke Theresa , Hökby Sebastian , Carli Vladimir , Hadlaczky Gergö
Published: January 2025

Introduction

Inadequate sleep duration and sleep‐related problems are highly prevalent among adolescents and pose a significant health risk during a critical development stage. This study seeks to explore associations between sleep and suicidal ideation among adolescents.

Methods

Cross‐sectional questionnaire data from the baseline wave (2016‐2018) of a cohort of 12‐ to 16‐year‐old Swedish adolescents (n = 4433, 50.39% girls) were analyzed. A split‐sample approach was used for exploratory analyses and model selection. Logistic regression was used to estimate the associations between suicidal ideation and self‐reported sleep parameters (weekday sleep duration, sleep quality), both adjusted and unadjusted for depression.

Results

Adolescents with suicidal ideation slept on average 60 min less on weekdays and reported worse sleep quality compared to those without suicidal ideation. Suicidal ideation was significantly associated with weekday sleep duration (p = 0.0267) and self‐perceived sleep quality (p = 0.0003). Associations remained after controlling for depression.

Conclusions

Sleep problems in adolescents are associated with suicidal ideation, beyond the effect of depression. Findings may have implications for screening and suicide prevention among clinical populations of adolescents, as well as for public health interventions aimed at promoting sleep and mental health in adolescents.
Qcforever2: Advanced Automation of Quantum Chemistry Computations
Authors: Sumita Masato , Terayama Kei , Ishida Shoichi , Suga Kensuke , Saito Shohei , Tsuda Koji
Published: January 2025

QCforever is a wrapper designed to automatically and simultaneously calculate various physical quantities using quantum chemical (QC) calculation software for blackbox optimization in chemical space. We have updated it to QCforever2 to search the conformation and optimize density functional parameters for a more accurate and reliable evaluation of an input molecule. In blackbox optimization, QCforever2 can work as compactly arranged surrogate models for costly chemical experiments. QCforever2 is the future of QC calculations and would be a good companion for chemical laboratories, providing more reliable search and exploitation in the chemical space.
Descriptive Epidemiology and Prognostic Significance of Diaphragm Thickness in the General Population: The Nagahama Study
Authors: Tabara Yasuharu , Matsumoto Takeshi , Murase Kimihiko , Kawaguchi Takahisa , Setoh Kazuya , Wakamura Tomoko , Hirai Toyohiro , Chin Kazuo , Matsuda Fumihiko
Published: January 2025

Background

Diaphragm thickness is a potential marker of sarcopenia in addition to muscle mass and strength at extremities. We aimed to clarify the descriptive epidemiology and prognostic significance of diaphragm thickness in the general population.

Methods

The study participants were 3324 community residents (mean age: 61.4 ± 12.8 years) who participated in a longitudinal cohort study. Clinical parameters were obtained during the follow‐up survey of the study population. Diaphragm thickness was measured from B‐mode ultrasound images obtained in a supine position. Clinical and physical factors independently associated with diaphragm thickness were assessed by a linear regression model and a causal mediation analysis. All‐cause mortality was determined by reviewing residential registry records. Prognostic significance of diaphragm thickness for all‐cause mortality was examined using a Cox proportional hazard model analysis.

Results

Diaphragm thickness was greater in men than women (end‐expiration, β = 0.161, p < 0.001; end‐inspiration, β = 0.156, p < 0.001) and associated with waist circumference (end‐expiration, β = 0.259, p < 0.001; end‐inspiration, β = 0.128, p < 0.001). Handgrip strength, smoking habit, insulin resistance and exercise habit were not associated with diaphragm thickness. Skeletal muscle mass index showed apparent association with diaphragm thickness, though this association was not observed after adjusting for waist circumference. Over a mean follow‐up of 1686 days (15 358 person‐years), there were 56 cases of all‐cause mortality. Weak handgrip strength (hazard ratio = 0.95, p = 0.044) and low forced vital capacity (hazard ratio = 0.57, p = 0.045) were associated with all‐cause mortality, though none of the diaphragm thickness parameters showed a significant association (thickness at end‐expiration, p = 0.722; thickness at end‐inspiration, p = 0.277; thickening fraction, p = 0.219).

Conclusions

Waist circumference but not parameters of sarcopenia was independently associated with diaphragm thickness. Diaphragm thickness was not associated with all‐cause mortality. Diaphragm thickness may not be a marker of systemic sarcopenia.
Transcriptomic Profiling Reveals 17β‐Estradiol Treatment Represses Ubiquitin‐Proteasomal Mediators in Skeletal Muscle of Ovariectomized Mice
Authors: Kararigas Georgios , Ebeling Mara C. , Le Gengyun , Lai Shaojuan , Cui Chunmei , Cui Qinghua , Lowe Dawn A.
Published: January 2025

Background

With a decline of 17β‐estradiol (E2) at menopause, E2 has been implicated in the accompanied loss of skeletal muscle mass and strength. We aimed at characterizing transcriptomic responses of skeletal muscle to E2 in female mice, testing the hypothesis that genes and pathways related to contraction and maintenance of mass are differentially expressed in ovariectomized mice with and without E2 treatment.

Methods

Soleus and tibialis anterior (TA) muscles from C57BL/6 ovariectomized mice treated with placebo (OVX) or E2 (OVX + E2) for 60 days, or from skeletal muscle‐specific ERα knockout (skmERαKO) mice and wild‐type littermates (skmERαWT), were used for genome‐wide expression profiling, quantitative real‐time PCR and immunoblotting. Computational detection of estrogen response elements (EREs) was performed with EREFINDER.

Results

We found 155 significantly regulated probe sets in response to E2 (p ≤ 0.001). Pathway analyses identified proteasome and ubiquitin‐mediated proteolysis as two downregulated pathways in the E2 group. We confirmed downregulation (p ≤ 0.05) in levels of Fbxw7, Psmb6, Ube2h and Ubxn1, as well as pro‐apoptotic Bnip3 and inflammatory factor Nfkbia. Computational analysis identified ERE in the promoter regions of Psmb6, Ube2h, Bnip3 and Nfkbia. The overall content of ubiquitinated proteins was modestly but significantly lower in TA muscles from OVX + E2 vs. OVX mice (p = 0.039). There were no differences between skmERαKO and skmERαWT mice or between skmERαKO/OVX and skmERαKO/OVX + E2 mice for any genes assessed, indicating that ERα is required for E2 regulation of those genes.

Conclusions

These results suggest that a mechanism whereby E2 protects against losses of skeletal muscle mass and strength is regulation of ubiquitin‐proteasomal mediators.
Ultrasound‐Based Local Lung Motion Assessment Using Synthetic Lateral Phase
Authors: Fung Christopher M. , Rubin Jonathan M. , Gao Jing , Hamilton James D.
Published: January 2025

Background

Ultrasound lung surface motion measurement is valuable for the evaluation of a variety of diseases. Speckle tracking or Doppler‐based techniques are limited by the loss of visualization as a tracked point moves under ribs or is dependent.

Methods

We developed a synthetic lateral phase‐based algorithm for tracking lung motion to overcome these limitations. To validate the technique, we generated simulated lung motion images. We also obtained lung ultrasound cines from a healthy volunteer and a mechanically ventilated COVID‐19 patient. In the healthy volunteer, the respiratory pattern varied between breath‐hold, regular, and rapid shallow breathing.

Results

The measured displacement was within 3% of the ground truth for simulated cines. In both the healthy volunteer and COVID‐19 patients, measured displacement was greatest in the lower and lateral zones of the lung when the ipsilateral side was compared. In the healthy volunteer, when the respiratory pattern was varied, measured displacement was greater in regular breathing compared to rapid shallow breathing and compared to breath‐hold patterns in both the upper and lower lung zones.

Conclusion

Estimation of lung surface displacement using a synthetic lateral phase‐based approach is feasible. Future human studies should validate this approach against a direct measurement of lung surface movement.
Incidence and Risk Factors for Varicella‐Zoster Virus‐Associated Central Nervous System Infections: A Nationwide Swedish Retrospective Case‐Control Study
Authors: Tyrberg Tobias , Hagberg Lars , Nilsson Staffan , Grahn Anna
Published: January 2025

The determinants of varicella‐zoster virus (VZV)‐associated central nervous system (CNS) infection have not been fully elucidated. This study aimed to investigate the incidence and risk factors, including immunosuppression, for different manifestations of VZV‐associated CNS infection. Patient registers were used to include adults diagnosed with VZV‐associated CNS infections between 2010 and 2019 in Sweden. Nationwide registers covering specialized care, and regional registers covering primary care, were used. Controls without a VZV diagnosis during the study period were matched by age and sex. Risk factors were calculated using multivariable logistic regression. A total of 1488 adult cases with VZV‐associated CNS infection were identified, yielding an incidence of 1.92/100 000 person‐years, which increased over the study period. Meningitis was the most frequent (45%), followed by encephalitis (38%), and Ramsay Hunt syndrome (17%). The highest incidence was observed in individuals over 70 years of age (4.15/100 000 person‐years), in whom encephalitis was most common. Statistically significant risk factors for VZV‐associated CNS infection were HIV, hematological cancer, treatment with specific immunosuppressants or glucocorticoids, chronic obstructive pulmonary disease, diabetes, solid cancer, stroke, and congestive heart failure. Encephalitis was associated with older age, more immunosuppressive conditions, and more comorbidities than other manifestations. In conclusion, VZV is a common cause of adult viral CNS infection, for which elderly individuals with immunosuppressive or comorbid conditions are at the highest risk. The strongest risk factors found were HIV, hematological cancer, and treatment with specific immunosuppressants or high‐dose glucocorticoids.
Interleukin‐12/23 and Interleukin‐23 Inhibitors for the Treatment of Cutaneous Crohn's Disease: A Case Series From a Multi‐Institutional Registry
Authors: McKay G. E. , Coromilas A. , Liu L. , Shaw K. S. , Murphy M. , Punyamurthy N. , Soltero K. M. Santiago , Damsky W. , Wanat K. A. , Charrow A. P. , Rosenbach M. , Caplan A. , LaSenna C. E. , Arkin L. , Shields B. E.
Published: January 2025

Background

Cutaneous Crohn's disease (CCD) is a granulomatous condition of the skin discontiguous from the gastrointestinal tract. Cutaneous disease rarely correlates with intestinal disease and often requires separate treatment. While the use of interleukin‐12/23 (IL‐12/IL‐23) and interleukin‐23 (IL‐23) inhibitors is FDA‐approved for intestinal Crohn's disease (CD), there is limited data for CCD. We retrospectively reviewed the clinical features of 24 cases of CCD treated with risankizumab as monotherapy, ustekinumab as monotherapy, or ustekinumab in combination with vedolizumab from seven academic institutions across the United States.

Objectives

The objective of this study was to evaluate the impact of IL‐12/23 or IL‐23 inhibitor therapy on CCD independent of intestinal disease.

Methods

Patients were identified by retrospective review of the electronic health record including histopathologic diagnosis consistent with CCD. At least one visit with a dermatologist between 2000 and 2020 was required. Chart review collected demographic, clinical and histologic data.

Results

We identified 24 adult and paediatric patients with CCD treated with IL‐12/IL‐23 inhibitor therapy. Most patients were White (21/24, 88%), female (20/24, 83%), had intestinal CD (19/24, 79%), were diagnosed with intestinal CD before CCD diagnosis (18/24, 75%), and were on biologic therapy before CCD diagnosis (16/24, 67%). Most patients failed to respond to treatment with anti‐tumour necrosis alpha (anti‐TNF) therapy before IL‐12/IL‐23 inhibitor therapy (22/24, 92%). Of the 24 patients treated with ustekinumab, less than half (7/24, 29%) were simultaneously treated with vedolizumab. Four adult patients (4/24, 17%) were treated with risankizumab monotherapy. At the date of the last follow‐up with a dermatologist, over a third (8/24, 33%) of patients' skin was reported as complete clearance by physician note.

Conclusions

We propose that IL‐12/IL‐23 and IL‐23 inhibitor therapy be considered as therapy for the treatment of TNF‐blockade refractory CCD.
Systematic Review of Granulomatous Invasive Fungal Sinusitis Management
Authors: Baqays Abdulsalam , Almutawa Sarah , Alsabti Razan , Alsughayer Luluh , Campbell Sandra , Almaflehi Nassr , Albaharana Hussain , Alsaleh Saad
Published: January 2025

Objectives

Granulomatous invasive fungal sinusitis (GIFS) affects immunocompetent individuals. There is ongoing debate over whether surgery, antifungal medication, or a combined approach is the best treatment. This article summarizes reports about GIFS and its management.

Methods

Eight search engines, gray literature, and review articles were searched. Two independent reviewer groups screened the eligibility of articles. An independent reviewer solved disagreements. Exclusion criteria included non‐English language reports, papers with unavailable full‐texts, reviews, publications before 1980, and studies lacking information about GIFS management.

Results

Of the 279 identified articles, 41 studies were included (n = 89 patients). Sinonasal GIFS with skull‐base/intracranial extension was associated with an increase in mortality (p = 0.002, OR = 14.083; 95% CI = 1.753–113.157). Treatment was associated with an 87.2% remission rate (p < 0.001, OR = 7.818; 95% CI = 4.502–13.576); a combined medical and surgical approach had a 74.2% recovery rate. Of surgical interventions, the highest recovery rates were associated with endoscopic debulking (52.5%), extensive surgical debulking (32.5%), and open sinonasal approach (15%, p = 0.132). The utilization of voriconazole was associated with higher recovery rates, but this was not significant (76.9 vs. 56%, p = 0.548).

Conclusion

Sinonasal GIFS with skull‐base/intracranial extension is associated with higher mortality rates. The superiority of the endoscopic debulking and voriconazole protocol in managing these cases warrants further investigation.

Level of Evidence

Level 4.
Early Severe Cortical Involvement and Novel FUCA1 Mutations in a Pediatric Fucosidosis Case
Authors: de la Peña Mar Jiménez , López‐Martín Sara , Fernández‐Mayoralas Daniel Martín , Fernández‐Perrone Ana Laura , Jiménez de Domingo Ana , Tirado Pilar , Calleja‐Pérez Beatriz , Álvarez Sara , Albert Jacobo , Fernández‐Jaén Alberto
Published: January 2025

Background

Biallelic pathogenic variants in the FUCA1 gene are associated with fucosidosis. This report describes a 4‐year‐old boy presenting with psychomotor regression, spasticity, and dystonic postures.

Methods and Results

Trio‐based whole exome sequencing revealed two previously unreported loss‐of‐function variants in the FUCA1 gene. Brain magnetic resonance imaging (MRI) findings included corpus callosum hypoplasia, white matter hypomyelination, and alterations in the globus pallidi, alongside markedly reduced cortical thickness.

Conclusions

These findings suggest that cortical atrophy may occur in the early stages of fucosidosis. Early diagnosis is imperative for genetic counseling, timely investigations, and initiating early therapeutic interventions to potentially mitigate more extensive brain involvement.
Amid federal lawsuit, groups cite opposing views of MHPAEA final rule
Authors: Canady Valerie A.
Published: January 2025

Pointing to major concerns regarding the Mental Health Parity and Addiction Equity Act (MHPAEA) final rule issued Sept. 9, 2024, the ERISA Industry Committee (ERIC) on Jan. 17 filed a lawsuit against federal agencies alleging that the new regulations violate due process, and are arbitrary and capricious. ERIC alleges that the final parity rules “overstep” existing parity law.
Study: Social health can improve lives of people with SMI
Authors: Canady Valerie A.
Published: January 2025

Social health — the quality and quantity of social interactions, relationships, and support networks — can put social aspects of patients' lives on par with physical and mental aspects in a comprehensive understanding of health, say the authors of a new article published online January 22 in JAMA Psychiatry.
Ephrin A1 ligand‐based CAR‐T cells for immunotherapy of EphA2‐positive cancer
Authors: Liu Nan , Wei Wenwen , Ren Kexing , Liang Dandan , Yang Dong , Zhang Weishan , Yang Beibei , Sun Bin , Zhao Jincheng , Cao Dan , Zou Liqun , Zhao Xudong
Published: January 2025

Chimeric antigen receptor (CAR) T cells have demonstrated promising results in hematological malignancies; however, challenges remain in treating solid tumors. New CARs with more effectiveness and lower side effects are needed. Ephrin type‐A receptor 2 (EphA2) belongs to the Ephrin family of receptor tyrosine kinases, which is overexpressed in several solid malignancies. Compared with some single‐chain variable fragment (ScFv) CARs that exhibit excessively high affinity for their targets, natural receptor/ligand‐based CARs maintain inherent affinity for their binding partners, potentially balancing cytotoxicity and side effects to better meet clinical needs. Here, we designed a CAR targeting EphA2‐positive cancer cells by exploiting the extracellular domain of its natural ligand Ephrin A1 (EFNA1). EFNA1 CAR‐T cells exhibited specific cytotoxicity against various cancer cells and cancer stem‐like cells in vitro, and significantly suppressed tumor growth in a pancreatic cancer xenograft mouse model. Moreover, although these CAR‐T cells specifically targeted mouse EphA2 and killed mouse tumor cell lines in vitro, they did not induce obvious side effects in mice. Additionally, it also showed good safety in rhesus macaques. Collectively, these results validate the therapeutic effectiveness and safety of EFNA1 CAR‐T cells for treating solid tumors.
A Comparative Study of Risk Factors for Falls in Total Hip and Knee Arthroplasty Patients and Community‐Dwelling Older Adults
Authors: Chen Serena Kuangyi , Voaklander Don , Jhangri Gian S. , Jones C. Allyson
Published: January 2025

Objectives

Falls in older adults are a public health concern, yet little is known about falls in adults with hip or knee total joint arthroplasty (TJA) who may be at a higher risk than the general population. The study objectives were to compare the number of fallers and fear of falling in TJA patients to age and sex matched community controls, and determine whether the type of risk factors for falls reported in TJA differed from the community group.

Methods

A cross sectional comparative study was conducted with patients waiting or recovering from TJA and age and sex matched comparison group of older adults residing in the community. Reported falls and risk factors for falling were compared to age and sex matched controls from the community. Fear of falling was measured using the Activities‐specific Balance Confidence (ABC) Scale. Logistic regression was used to determine risk factors associated with falls in TJA and community participants.

Results

Of the 198 TJA participants, 29% (n = 57) reported falls within the past 12 months compared to 24% (n = 24) of 100 participants in the control group (p = 0.36). Of those who fell, 25 (44%) were recurrent fallers in the TJA cohort compared with 6 (25%) in the community cohort. Eleven participants reported falls after TJA surgery. Fear of falling was greater in the TJA group (ABC score, mean ± SD: 67.1 ± 24.4) than in the community group (88.1 ± 14.9) (p < 0.001).

Conclusion

Although the number of participants who reported falls was comparable in both groups, the TJA group had more recurrent falls, different risk factors for falls, and more fear of falling. Fall prevention programs should be embedded in pre‐operative programs for patients undergoing surgery for TJA.
Likes and Hashtags: Exploring the Potential Relationship Between Social Media use and the Emotional Wellbeing of Oncology Professionals
Authors: Moerdler Scott , Yan Yufei , Chrysanthopoulou Stavroula , Barry Maura , Henry Elizabeth , Lucas Tiffany , Marshall Ariela , Dizon Don S.
Published: January 2025

Purpose

To explore the potential relationship between social media (SoMe) and burnout or overall wellbeing within the field of oncology.

Design

A cross‐sectional study of adult and pediatric oncology professionals conducted using an anonymous electronic survey. The survey was disseminated through the Children's Oncology Group (COG) and the SWOG Cancer Research Network (SWOG) member listservs.

Results

The majority of pediatric and adult oncology professionals are not engaging on, with only 873/3000 (29%) using SoMe professionally. Use of SoMe was associated with statistically significant higher incidence of self‐reported burnout and poorer self‐reported work‒life integration (WLI). However, both groups reported the same degree of career satisfaction and choosing the same career/job again. SoMe users and non‐users reported similar overall psychological distress, although the use of SoMe was associated with less severe psychological distress.

Conclusion

While SoMe users reported higher rates of burnout and poorer WLI compared to non‐users, it was not accompanied by higher levels of psychological distress. Furthermore, there were no differences in career satisfaction. These misalignments require further study.