bluuebunny/crossref_metadata_2025 huggingface dataset:
Augmentation invariant manifold learning
Authors: Wang Shulei
Published: January 2025

Data augmentation is a widely used technique and an essential ingredient in the recent advance in self-supervised representation learning. By preserving the similarity between augmented data, the resulting data representation can improve various downstream analyses and achieve state-of-the-art performance in many applications. Despite the empirical effectiveness, most existing methods lack theoretical understanding under a general nonlinear setting. To fill this gap, we develop a statistical framework on a low-dimensional product manifold to model the data augmentation transformation. Under this framework, we introduce a new representation learning method called augmentation invariant manifold learning and design a computationally efficient algorithm by reformulating it as a stochastic optimization problem. Compared with existing self-supervised methods, the new method simultaneously exploits the manifold’s geometric structure and invariant property of augmented data and has an explicit theoretical guarantee. Our theoretical investigation characterizes the role of data augmentation in the proposed method and reveals why and how the data representation learned from augmented data can improve the k-nearest neighbour classifier in the downstream analysis, showing that a more complex data augmentation leads to more improvement in downstream analysis. Finally, numerical experiments on simulated and real data sets are presented to demonstrate the merit of the proposed method.
A rare case of unexplained recurrent intracerebral haemorrhage
Authors: Cao Bo B , Wang Jinlong J , Ren Qinguang Q
Published: January 2025

Recurrent intracerebral haemorrhage (ICH) presents a complex clinical challenge that eludes traditional diagnostic and treatment approaches. We report a rare and unexplained case of a middle-aged patient with recurrent ICH, for which extensive multidisciplinary investigations have yet to provide a definitive diagnosis or an effective long-term treatment strategy. Intraoperative pathology, genetic testing, cerebral angiography, inflammatory markers (erythrocyte sedimentation rate, C-reactive protein), specific antibodies (ANCA, anti-nuclear antibodies), and immunoglobulin levels showed no specific positive findings. This case highlights the limitations of current diagnostic and therapeutic modalities in recurrent ICH. Further research into the genetic and molecular underpinnings of recurrent ICH is needed to enhance diagnostic accuracy and develop targeted therapies for similar cases.
Efficacy of anifrolumab in systemic lupus erythematosus patients with serological manifestations: A post hoc analysis of the Japan subgroup of the TULIP-2 trial
Authors: Tanaka Yoshiya , Atsumi Tatsuya , Okada Masato , Miyamura Tomoya , Ishii Tomonori , Nishiyama Susumu , Matsumura Ryutaro , Hayashi Nobuya , Matsumoto Takahiro , Yabe-Wada Toshiki , Yamaguchi Yoshiyuki , Abreu Gabriel , Lindholm Catharina , Takeuchi Tsutomu
Published: January 2025

Objectives

To describe the efficacy of anifrolumab versus placebo in Japanese systemic lupus erythematosus (SLE) patients with low complement (C3 or C4) and/or who are positive for anti-double stranded DNA antibodies.

Methods

This was a descriptive post hoc analysis of Japanese SLE patients with serological manifestations in the Treatment of Uncontrolled Lupus via the Interferon Pathway-2 (TULIP-2) trial who received either anifrolumab or placebo.

Results

Of the 43 patients enrolled, 79.2% (19/24) and 73.7% (14/19) had low C3, low C4, and/or were positive for anti-double stranded DNA antibodies at baseline in the anifrolumab and placebo groups, respectively. At Week 52, 52.6% (10/19) and 7.1% (1/14) patients in the anifrolumab and placebo groups, respectively, achieved a British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response. The proportion of patients who tapered their glucocorticoid (GC) dose throughout the study, without increasing their dose, or who sustained baseline GC doses of ≤7.5 mg/day was numerically higher in the anifrolumab group [78.9% (15/19)] than in the placebo group [50.0% (7/14)].

Conclusions

In line with the clinical profile of anifrolumab in the TULIP-2 study, the efficacy of anifrolumab was shown in Japanese SLE patients with serological manifestations achieving a BICLA response, and with tapered GC dose or sustained GC doses of ≤7.5 mg/day.
A Smart Millimeter-Wave Base Station for 6G Application Based on Programmable Metasurface
Authors: Zhang Jun Wei , Qi Zhen Jie , Wu Li Jie , Zhou Qun Yan , Dai Jun Yan , Cao Wan Wan , Ge Xiao , Gao Cheng Long , Gao Xinxin , Wang Si Ran , Wang Zheng Xing , Fang Yao Li , Wu Jun Wei , Zhang Jia Nan , Cui Tie Jun , Cheng Qiang
Published: January 2025

The evolution of programmable metasurfaces has yielded many exciting electromagnetic (EM) phenomena and applications in both physical and information communities. Programmable metasurfaces, also known as reconfigurable intelligent surfaces (RISs) or intelligent reflecting surfaces (IRSs) in wireless communications, have played important roles in enhancing signal coverage and transmission quality and in building an artificially controlled communication environment. However, most of the realistic implementations are designed in the sub-6G band with a small array scale and 1-bit phase control ability, making the performance improvement not marvelous compared to the traditional solutions. Here, we propose a large-scale 2-bit millimeter-wave programmable metasurface to build an integrated smart base station framework for 6G communications. The meta-array is composed of 30×30 meta-elements, each with two embedded PIN diodes. A dish cone antenna is integrated with the metasurface to serve as the feeding source. A control board is designed to autonomously switch the working states of the entire 1800 PIN diodes based on a field programmable gate array, enabling the individual adjustment of the EM responses of all meta-elements in the array. Through the deliberate arrangement of phase distribution on the surface, the array can undergo reconfiguration to achieve the desired EM functionalities. We take the programmable metasurface as the core to assist a millimeter-wave base station and validate its good performance of wireless communications in a realistic in-door scenario. Subsequently, we build a four-stream wireless communication scenario using four 30×30 arrays and demonstrate smart multi-user information transmissions with different positions. This work provides great potential for programmable metasurfaces to aid the development of novel and intelligent millimeter-wave base stations, offering valuable insights for advancing next-generation mobile communications.
Shift work, thyroid function and liver function among subway workers
Authors: Yu F , Liu J , Qu T , Zhao M , Wang J , Jiang S , Ge L , Ye F , Liu L , He Z , Zhang S
Published: January 2025

Background

Shift work is associated with an increased risk of liver injury. However, whether and how shift work alters liver function remains unclear.

Aims

This study aimed to investigate the associations between shift work and the liver function parameters, and further explore the mediating roles of thyroid function indicators.

Methods

We conducted a cross-sectional study involving a convenience sample of 724 subway workers. Multivariate linear regression models were adopted to approximate the effect values for the associations of shift work with liver function parameters and thyroid function indicators. Mediation analyses were used to explore the roles of thyroid function indicators in the association between shift work and liver function parameters.

Results

Shift work was associated with increased levels of alkaline phosphatase (ALP), total triiodothyronine (TT3) and free thyroxine (FT4) (β = 6.309, 95% confidence interval [CI] 2.739–9.879, β = 0.328, 95% CI 0.242–0.415 and β = 2.913, 95% CI 1.502–2.884, respectively). In stratification analysis, the positive association between shift work and TT3, FT3 and FT4 was more pronounced among people >30 years old. The increase in shift worker FT3 and aspartate transaminase levels was stronger among alcohol users. Mediation analysis showed that TT3 and FT4 mediated 39% and 29% of the associations between shift work and the increased level of ALP, respectively (all P < 0.05).

Conclusions

The results suggest that shift work is associated with increased ALP levels of subway workers, which is partly mediated by the increase of TT3 and FT4 levels.
The pathologic and genomic evolution of primary malignant phyllodes tumors of the breast: retrospective cohort study and case-control genomic analysis
Authors: Valenza Carmine , Trapani Dario , Porta Francesca Maria , Olmeda Edoardo , Gaeta Aurora , Boscolo Bielo Luca , Conversano Federica , De Pas Tommaso Martino , Castellano Grazia , Santoro Celeste , Battaiotto Elena , Mane Eltjona , Coppola Sara , Conforti Fabio , Mattar Denise , Gandini Sara , Veronesi Paolo , Guerini Rocco Elena , Pennacchioli Elisabetta , Curigliano Giuseppe
Published: January 2025

Background

In patients with phyllodes tumors of the breast, the presence of mediator of RNA polymerase II transcription subunit 12 homolog mutations (MED12m) and a history of previous fibroadenoma may predict better outcomes. To aid in the prognostication of malignant phyllodes tumors of the breast (B-MPT), we assessed the prognostic value of fibroadenoma-like areas (supposed to have stemmed from a pre-existing fibroadenoma) and MED12m, in patients with resected primary B-MPTs.

Methods

We conducted a single-center, retrospective, cohort study including all consecutive patients aged ≥18 years old, with non-metastatic B-MPT, who underwent surgery from January 2000 to December 2021. The endpoints were the cumulative incidences of all recurrences, according to the presence of fibroadenoma-like areas, reviewed by 3 reference pathologists. A nested, case-control genomic analysis was performed to evaluate the association between MED12m, the presence of fibroadenoma-like areas, and cancer recurrences.

Results

Eight-nine patients were included, with 47% of tumors exhibiting Fibroadenoma-Like Areas (FLA+). These areas were not significantly associated with local recurrence (5-year cumulative incidence in FLA+ vs FLA-: 13.0, 95%CI [4.6-25.9] vs 23.6, 95%CI [11.9-37.5]; P = .14) or distant recurrence (5-year cumulative incidence in FLA+ vs FLA-: 12.5, 95%CI [4.5-25.0] vs 8.9, 95%CI [2.8-19.5], P = .61), at a median follow-up of 6.7 years. MED12m was not associated with distant recurrences or the presence of fibroadenoma-like areas.

Conclusions

Half of B-MPTs are characterized by the presence of fibroadenoma-like areas. This pathologic feature is not significantly associated with lower distant and local recurrences nor with the presence of MED12 mutations.
Health Capital and its Significance for Health Justice
Authors: Davies Ben , Schramme Thomas
Published: January 2025

This paper outlines a novel framing of the normative significance of health by considering the idea of ‘health capital’. Health capital is a set of health-related assets of individuals that enable them to pursue their interests and to collaborate with others. The specific contribution of this paper is to establish the notion of health capital beyond a metaphorical idea and to initially explore the repercussions of it for theories of health justice. We propose a sufficientarian approach to health capital justice. Our theory claims that social justice requires enabling people to achieve enough health capital to meet threats to health. This is a dynamic ideal, establishing claims of justice over time. The overarching goal is to avoid disadvantageous tipping points of health depletion.
Association of fibrinogen-to-albumin ratio with all-cause and cardiovascular mortality in patients on dialysis with acute coronary syndrome
Authors: Xie Enmin , Wu Yaxin , Ye Zixiang , Zhao Xuecheng , Li Yike , Shen Nan , Wang FanFan , Gao Yanxiang , Zheng Jingang
Published: January 2025

Purpose

This study aimed to investigate the association of the fibrinogen-to-albumin ratio (FAR) and all-cause mortality as well as cardiovascular mortality in patients on dialysis with acute coronary syndrome (ACS). Furthermore, we explored the incremental prognostic value of incorporating the FAR into the Global Registry of Acute Coronary Events (GRACE) score.

Methods

We retrospectively enrolled 1035 patients on dialysis with ACS between January 2015 and June 2021. The primary outcome was all-cause mortality, and the secondary outcome was cardiovascular mortality. Multivariate Cox regression model, restricted cubic spline analysis, and C-statistic were performed to evaluate the prognostic value of FAR on outcomes.

Results

After a median follow-up of 21.8 months, 369 (35.7%) patients died, including 250 cardiovascular deaths. Patients with the highest FAR tertile had significantly increased risks of all-cause mortality (46.1% vs 27.8%; adjusted hazard ratio [HR], 1.790; 95% confidence interval [CI], 1.372–2.336) and cardiovascular mortality (33.0% vs 16.5%; adjusted HR, 2.086; 95% CI, 1.496–2.908) compared to those in the lowest tertile. Restricted cubic spline analysis revealed a J-shaped association between the FAR and all-cause mortality and cardiovascular mortality, with HRs increasing significantly when the FAR exceeded 94.15. Furthermore, integrating the FAR into the GRACE score significantly improved its predictive accuracy for all-cause mortality and cardiovascular mortality, as measured by C-statistic, continuous net reclassification index, and integrated discriminatory index.

Conclusions

In patients on dialysis with ACS, the FAR was independently associated with increased risks of all-cause mortality and cardiovascular mortality. Incorporating the FAR might improve the predictive accuracy of the GRACE score in patients on dialysis with ACS.
There is more to national economies than the national economy: extending the Growth Model research programme in comparative political economy
Authors: Regan Aidan , Blyth Mark
Published: January 2025

This article argues that the Growth Model (GM) research programme in comparative political economy has an ontological and methodological bias towards the national level that generates an implicit functionalist-reductionism. This is a problem because GM research is explicitly designed to be a theory that eschews the functionalist-equilibrium New Keynesian assumptions of Varieties of Capitalism theory. To overcome this problem, we make the case that focusing on the city-regional level within a global-systems level analysis allows for a better integration of comparative political economy with international political economy in GM research. In particular, we argue that focusing on where income growth is produced and concentrated within advanced capitalism (cities-regions) allows us to better explain the political consequences of unequal growth from a post-Keynesian GM-perspective.
A Novel Computational Machine Learning Pipeline to Quantify Similarities in Three-Dimensional Protein Structures
Authors: Hirway Shreyas U , Xu Xiao , Fan Fan
Published: January 2025

Animal models are widely used during drug development. The selection of suitable animal model relies on various factors such as target biology, animal resource availability and legacy species. It is imperative that the selected animal species exhibit the highest resemblance to human, in terms of target biology as well as the similarity in the target protein. The current practice to address cross-species protein similarity relies on pair-wise sequence comparison using protein sequences, instead of the biologically relevant 3-dimensional (3D) structure of proteins. We developed a novel quantitative machine learning pipeline using 3D structure-based feature data from the Protein Data Bank, nominal data from UNIPROT and bioactivity data from ChEMBL, all of which were matched for human and animal data. Using the XGBoost regression model, similarity scores between targets were calculated and based on these scores, the best animal species for a target was identified. For real-world application, targets from an alternative source, ie, AlphaFold, were tested using the model, and the animal species that had the most similar protein to the human counterparts were predicted. These targets were then grouped based on their associated phenotype such that the pipeline could predict an optimal animal species.
Improving Resident Physician History and Physical in Challenging Situations
Authors: Rockwell Nicholas , Tofil Nancy M. , Rutledge Chrystal , Gaither Stacy L. , Norwood Carrie , Zinkan J. Lynn , Aban Inmaculada , Willig James , Kong Michele
Published: January 2025

Objective:

To educate physician trainees using simulation on best management of children with autism spectrum disorder who have neurocognitive and behavioral challenges when experiencing acute illness.

Method:

A simulation-based curriculum including baseline assessment, communication techniques, and use of calming resources was developed to educate residents in assessing children with sensory barriers. Traditional simulation and deliberate practice were used to teach this curriculum to second- and third-year pediatric and internal medicine-pediatric residents. Using alternating assignment, residents were placed into 3 groups: deliberate practice, traditional simulation-based debriefing, and control (no simulation training). The residents were assessed on the initial visit, 2 weeks and 4 to 6 months follow-up periods with a sensory assessment tool. Assessment scores were analyzed using a general linear mixed model with random intercept based on Poisson regression to approximate distribution of the total score.

Results:

Forty-three residents participated: 46.5% men, 53.5% women. There were 15, 16, and 12 residents in the control, deliberate practice and traditional simulation groups, respectively. Both teaching styles showed improved performance at 2 weeks follow-up. In addition, these groups demonstrated higher performance when compared with the control group. We were able to show that resident physicians were able to learn important principles and retain them during 4 to 6 months follow-up. However, there was not a difference between 2 teaching styles both in improvement and retention.

Conclusion:

Simulation education, both deliberate and traditional, can be used to enhance teaching of key components in assessing children with sensory and communication barriers, including those with autism spectrum disorder when presenting with acute illness.
Embedding Universal Language Promotion in Pediatric Primary Care to Optimize Early Child Development and Reduce Long-Term Health Disparities
Authors: Salley Brenda , von Bevern Heather , Grasley-Boy Nicolette , Fleming Kandace , Weltmer Kirsten , Carta Judith
Published: January 2025

Objective:

To report on the feasibility and outcomes of universal language promotion intervention (Talk With Me Baby [TWMB]) embedded within routine well-child care for children from birth to 3-years old.

Methods:

Across 2 primary care clinics, 29 health care team members participated in a 12-month trial to deliver TWMB within well-child care visits. Feasibility was based on clinician feedback during the trial, clinician knowledge assessments, and clinic data. Sixty-three parents and their infant/toddlers were enrolled to provide feedback on TWMB and to assess parent language promotion behaviors, specifically, parents' self-reported use of their language-building interactions during daily activities with their child.

Results:

Clinician feedback and clinic data support TWMB as an acceptable and feasible intervention that can be used successfully within standard of care well-child visits by health care teams. Initial outcome data show positive changes for increasing parent-child language promoting interactions during daily activities.

Conclusion:

Results support the promise of leveraging primary care as a low-cost, scalable way to deliver universal language promotion intervention to optimize the developmental potential of all young children.
Recalcitrant Bilateral Volar Hand Burn Contracture in a Toddler Treated With Integra and Staged Full-thickness Skin Graft: A Literature Review
Authors: Yuen James C. , Wallace Jennifer L. , Steelman Susan C.
Published: January 2025

Background:

Recurrent burn contractures on the volar aspect of the hand present a formidable challenge, especially in the pediatric patient. We used Integra followed by staged full-thickness skin grafting for recurrent bilateral volar hand burn contracture in a toddler. We reviewed the literature to appraise the utility of full-thickness skin graft (FTSG) combined with Integra used for volar hand contractures.

Methods:

A systematic review of the world’s literature was conducted identifying publications on the application of Integra and skin substitutes for palmar hand contractures and wounds, to include burn injuries. We describe a case of a pediatric patient with recurrent bilateral burn flexion contracture of the palm and digits treated with scar excision and application of Integra, followed by staged application of FTSG.

Results:

We identified 92 publications pertaining to volar hand defects or contractures managed with skin grafts, skin substitutes, and/or flaps. Ten articles referred to the use of Integra on volar hand wounds or contractures, and only 2 articles used FTSG instead of split-thickness skin graft in combination with Integra. Our systematic review of volar burn injuries of the hand and fingers demonstrated that the use of Integra combined with FTSG for postburn flexion contracture of the hand has not been previously reported.

Conclusions:

This case report suggests that application of FTSG instead of split-thickness skin graft to vascularized Integra offers protective value against recurrent burn contracture of the palmar hand, but more studies are needed to support our hypothesis.
Streptococcus canis Rapidly Progressive and Fatal Neonatal Sepsis in a Term Infant
Authors: Saleh Ezzeldin , O’Neal Ashley , Torres Eunice , Vargas Laura , Rodriguez Marcela , Chaudhary Subhash
Published: January 2025

Background:

Streptococcus canis (S. canis), belonging to β-hemolytic group G streptococci, is increasingly reported to cause sepsis and severe infections in adults with comorbidities but is rarely reported in children.

Methods:

We describe a case of S. canis neonatal sepsis in a term infant with a rapidly fatal outcome. We reviewed the literature on neonatal infections due to all group G streptococci including S. canis.

Results:

We identified 10 articles describing 19 cases of neonatal sepsis due to group G streptococcus, of which only 3 cases were identified at the species level. Most patients presented in the first week of life with neonatal sepsis with bacteremia present in 90% of cases. Among the patients, gestational age ranged from 31 to 42 weeks. Prematurity was reported in 35% of the patients. All patients were treated with β-lactams with or without aminoglycosides. Mortality was 26%.

Conclusions:

S. canis infection is rare in the setting of neonatal sepsis; however, it can lead to high morbidity and mortality. It is imperative to promptly administer empiric antibiotics for critically ill neonates until neonatal sepsis is ruled out. β-lactams provide adequate coverage against S. canis. Further epidemiological and clinical studies focusing on S. canis are needed to fully understand the transmission and disease burden of this pathogen in neonates.
Impact of geriatric nutritional risk index on clinical outcomes in acute coronary syndrome patients: a comprehensive meta-analysis
Authors: Zhang Denghong , Tang Mingyang , Tang Nian , Earnest Benjamin Samraj Prakash , Ali Abdou Ihab Elsayed Mohamed
Published: January 2025

Background

The Geriatric Nutritional Risk Index (GNRI), derived from serum albumin levels and body weight relative to ideal body weight, is a novel tool for assessing nutritional status. This meta-analysis explored the association between GNRI and the clinical outcomes in patients with acute coronary syndrome (ACS).

Methods

We systematically searched PubMed, Embase, and Web of Science for studies evaluating the GNRI in patients with ACS. Inclusion criteria were observational studies reporting all-cause mortality or major adverse cardiovascular events (MACEs) among ACS patients categorized by low versus normal GNRI. Data extraction and quality assessment were independently performed by two authors, utilizing a random-effects model to account for potential heterogeneity.

Results

Eleven cohort studies, encompassing 18 616 patients with ACS, were included. A low GNRI was associated with significantly increased risks of all-cause mortality (RR, 1.95; 95% CI, 1.63–2.34; P < 0.001; I² = 32%) and MACEs (RR, 1.93; 95% CI, 1.62–2.29; P < 0.001; I² = 25%). Subgroup analyses for the all-cause mortality outcome showed consistent findings across varied study designs, patient demographics, and follow-up periods (P for subgroup differences all >0.05). Sensitivity analyses conducted by sequentially excluding individual studies confirmed the stability of these results.

Conclusion

A low GNRI at the time of admission is a significant predictor of increased all-cause mortality and MACEs in patients with ACS.
Evolution and factors associated with pediatric post-traumatic stress disorder 1 year after mild traumatic brain injury: a prospective, longitudinal study
Authors: Barak Sharon , Gerner Maya (Miriam) , Berant Ety , Silberg Tamar
Published: January 2025

Mild traumatic brain injury (mTBI) can lead to lasting adverse outcomes, including post-traumatic stress disorder (PTSD) or post-traumatic stress symptoms (PTSS). This study examined whether PTSD and PTSS can occur even after mTBI and tracked the evolution of PTSD in the long term. A total of 85 youth post-mTBI (median age: 10.00, 25–75th percentile: 8.50–2.62; 24% girls) and their mothers participated in this study. Assessments included PTSS/PTSD, postconcussion symptoms, loss of consciousness status, child’s anxiety, and maternal mental health, both shortly after mTBI (T1) and 1 year later (T2). Changes in PTSS scores from T1 to T2 were evaluated using the Wilcoxon test. T2 PTSS evolution was evaluated using correlations and partial correlations. To evaluate PTSD recovery trajectories, the percentage of youth in four recovery trajectories (chronic, delayed, recovery, and resilience) was calculated. Results showed a significant decrease in PTSS and PTSD rates from T1 (34%) to T2 (21%). PTSS at T2 was associated with PTSS and postconcussion symptoms at T1. After accounting for the child’s sociodemographic and clinical characteristics, the child’s self-reported PTSS at T1, along with self-reported postconcussion symptoms and symptom intensity, showed significant correlations with PTSS at T2 (r = 0.60, 0.32, and 0.37, respectively; P < 0.05). Most youth fell into the ‘resilient’ (40%) or ‘recovery’ (35%) groups, with only 6% showing ‘delayed’ recovery. One year after mTBI, 20% of the youth still experienced PTSD. In conclusion, this study highlights the need for long-term monitoring of youth after mTBI, as a notable proportion continue to experience enduring PTSD or PTSS.
Intravenous trazodone for the treatment of psychomotor agitation and associated symptoms in major depressive disorder patients experiencing a depressive episode with mixed features
Authors: Carmellini Pietro , Cuomo Alessandro , Pierini Caterina , Pardossi Simone , Pinzi Mario , Mariantoni Elisa , Fagiolini Andrea
Published: January 2025

Psychomotor agitation is a challenging symptom of major depressive disorder with mixed features (MDD-MF), often worsening outcomes and complicating treatment. This retrospective study assessed the efficacy and tolerability of intravenous trazodone in 97 hospitalized patients with MDE-MF. Symptom severity was evaluated using montgomery asberg depression rating Scale (MADRS), young mania rating scale, hamilton anxiety rating scale, GAD-7, and clinical global impression scale-severity of illness (CGI-S) scales, with significant reductions in agitation, anxiety, and irritability observed early during treatment. Correlation analyses revealed significant negative associations between intravenous (IV) trazodone dosage and improvements in MADRS (r = −0.23; P < 0.05), item 5 of GAD-7 (r = −0.27; P < 0.001), and CGI-S scores (r = −0.22; P < 0.05). Therapy duration also correlated negatively with improvements in GAD-7 item 5 (r = −0.29; P < 0.001) and CGI-S (r = −0.27; P < 0.001), indicating diminishing returns with prolonged treatment. Regression analyses showed that therapy duration, but not dosage, significantly influenced improvements in GAD-7 item 5 and CGI-S. Trazodone was well-tolerated, with only mild side effects in 11.3% of patients. These findings suggest that IV trazodone effectively reduces agitation and related symptoms in MDD-MF, particularly in the early treatment phase, emphasizing the importance of optimizing treatment duration. Future studies should investigate individualized dosing strategies and explore long-term outcomes in this population.
The cys-loop ligand-gated ion channel gene superfamily of the Colorado potato beetle,Leptinotarsa decemlineata
Authors: Chen Dongxu , Hawthorne David J.
Published: January 2025

Background

The insect cys-loop ligand-gated ion channel (cysLGIC) superfamily includes nicotinic acetylcholine receptors (nAChRs), γ-aminobutyric acid (GABA) receptors, glutamate- or histamine-gated chloride channels (GluCls and HisCls), pH-sensitive chloride channels (pHCls) and several other functionally uncharacterized receptors. Several of these receptors are target sites of neonicotinoids and other insecticides. Characterizing sequences of cysLGIC genes can facilitate the study of functional expression of subunits allowing insecticide/receptor interaction research, and can promote molecular resistance monitoring tools development. The Colorado potato beetle (CPB) is an agricultural pest that threatens the production of solanaceous crops. Although this insect shows frequent evolution of insecticide resistance, its cysLGIC superfamily is not well characterized.

Results

Twenty-two candidate CPB cysLGIC subunit genes were identified, and the functional regions of their protein sequences were annotated. CPB possesses 22 candidate cysLGIC subunit genes such as nAChR α4, nAChR α6, RDL, and GluCl subunits, with similar sequence, structure, and alternative exon use as that in other insects. RNA A-to-I editing was observed of nAChR α6. Two copies of the pHCl subunit gene were identified, the first duplication of this gene observed in insects.

Conclusion

The number of cysLGIC superfamily genes is similar to that of other insect species. Alternative splicing and RNA editing conserved in insect species were also identified in expected subunits, potentially contributing to structural and functional diversity of the receptor. Evidence of naturally truncated nAChR α4 and duplicated pHCl was observed, which invites future validation.
Integrating Hydrogen Exchange with Molecular Dynamics for Improved Ligand Binding Predictions
Authors: Walters Benjamin T. , Patapoff Alexander W. , Kiefer James A. , Wu Ping , Wang Weiru
Published: January 2025

We introduce Hydrogen-Exchange Experimental Structure Prediction (HX-ESP), a method that integrates hydrogen exchange (HX) data with molecular dynamics (MD) simulations to accurately predict ligand binding modes, even for targets requiring significant conformational changes. Benchmarking HX-ESP by fitting two ligands to PAK1 and four ligands to MAP4K1 (HPK1), and comparing the results to X-ray crystallography structures, demonstrated that HX-ESP successfully identified binding modes across a range of affinities significantly outperforming flexible docking for ligands necessitating large conformational adjustments. By objectively guiding simulations with experimental HX data, HX-ESP overcomes the long timescales required for binding predictions using traditional MD. This advancement promises to enhance the accuracy of computational modeling in drug discovery, potentially accelerating the development of effective therapeutics.
Defining the Polycystin Pharmacophore Through HTS & Computational Biophysics
Authors: Guadarrama Eduardo , Vanoye Carlos G. , DeCaen Paul G.
Published: January 2025

Background and Purpose

Polycystins (PKD2, PKD2L1) are voltage-gated and Ca2+-modulated members of the transient receptor potential (TRP) family of ion channels. Loss of PKD2L1 expression results in seizure-susceptibility and autism-like features in mice, whereas variants in PKD2 cause autosomal dominant polycystic kidney disease. Despite decades of evidence clearly linking their dysfunction to human disease and demonstrating their physiological importance in the brain and kidneys, the polycystin pharmacophore remains undefined. Contributing to this knowledge gap is their resistance to drug screening campaigns, which are hindered by these channels’ unique subcellular trafficking to organelles such as the primary cilium. PKD2L1 is the only member of the polycystin family to form constitutively active ion channels on the plasma membrane when overexpressed.

Experimental Approach

HEK293 cells stably expressing PKD2L1 F514A were pharmacologically screened via high-throughput electrophysiology to identify potent polycystin channel modulators. In-silico docking analysis and mutagenesis were used to define the receptor sites of screen hits. Inhibition by membrane-impermeable QX-314 was used to evaluate PKD2L1’s binding site accessibility.

Key Results

Screen results identify potent PKD2L1 antagonists with divergent chemical core structures and highlight striking similarities between the molecular pharmacology of PKD2L1 and voltage-gated sodium channels. Docking analysis, channel mutagenesis, and physiological recordings identify an open-state accessible lateral fenestration receptor within the pore, and a mechanism of inhibition that stabilizes the PKD2L1 inactivated state.

Conclusion and Implication

Outcomes establish the suitability of our approach to expand our chemical knowledge of polycystins and delineates novel receptor moieties for the development of channel-specific antagonists in TRP channel research.
Multi-center benchmarking of cervical spinal cord RF coils for 7 T MRI: A traveling spines study
Authors: Alonso-Ortiz Eva , Papp Daniel , Barry Robert L , Poëti Kyota , Seifert Alan C , Gilbert Kyle M , Lopez-Rios Nibardo , Paska Jan , Eippert Falk , Weiskopf Nikolaus , Beghini Laura , Graedel Nadine , Trampel Robert , Callaghan Martina F , Aigner Christoph S , Freund Patrick , Seif Maryam , Destruel Aurélien , Callot Virginie , Vannesjo Johanna , Cohen-Adad Julien
Published: January 2025

Purpose

The depth within the body, small diameter, long length, and varying tissue surrounding the spinal cord impose specific considerations when designing radiofrequency coils. The optimal coil configuration for 7 T cervical spinal cord MRI is unknown and, currently, there are very few coil options. The purpose of this work was (1) to establish a quality control protocol for evaluating 7 T cervical spinal cord coils and (2) to use that protocol to evaluate the performance of 4 different coil designs.

Methods

Three healthy volunteers and a custom anthropomorphic phantom (the traveling spines cohort) were scanned at seven 7 T imaging centers using a common protocol and each center’s specific cervical spinal cord coil. Four different coil designs were tested (two in-house, one Rapid Biomedical, and one MRI.TOOLS design).

Results

The Rapid Biomedical coil was found to have the highest B1+efficiency, whereas one of the in-house designs (NeuroPoly Lab) had the highest SNR and the largest spinal cord coverage. The MRI.TOOLS coil had the most uniform B1+profile along the cervical spinal cord; however, it was limited in its ability to provide the requested flip angles (especially for larger individuals). The latter was also the case for the second in-house coil (MSSM).

Conclusion

The results of this study serve as a guide for the spinal cord MRI community in selecting the most suitable coil based on specific requirements and offer a standardized protocol for assessing future coils.
On the need of individually optimizing temporal interference stimulation of human brains due to inter-individual variability
Authors: Brahma Tapasi , Guillen Alexander , Datta Abhishek , Huang Yu
Published: January 2025

Transcranial temporal interference stimulation (TI, TIS, or tTIS), also known as interferential stimulation (IFS), is able to focally stimulate deep brain regions, provided it is properly optimized. We previously presented an algorithm for optimizing TI using two arrays of electrodes and showed that it can achieve more focal stimulation compared to optimized high-definition transcranial electrical stimulation (HD-TES) and conventional optimized TI using two pairs of electrodes, especially in the deep brain areas such as the hippocampus. However, those modeling studies were only performed on an averaged head (MNI152 template) along with three individual heads. Existing TI work in the literature mostly does not optimize the stimulation but only utilizes a common (possibly optimized) montage of two pairs of electrodes on different individual heads. Here we aim to study the inter-individual variability of optimized TI by applying the same optimization algorithms on N = 10 heads using their individualized head models. Specifically, we compared the focality achieved by different stimulation techniques at three different regions of interest (ROI; right hippocampus, left dorsolateral prefrontal cortex, and left motor cortex). As expected, there is a variability in focality achieved by TI of up to 0.95 cm at the same ROI across subjects due to inter-individual differences in the head anatomy and tissue conductivity. Again we show that optimized TI using two arrays of electrodes achieve higher focality compared to optimized HD-TES at the same level of modulation intensity, especially at the deep brain locations. Compared to using a common montage obtained from a standard head (MNI152 template), individually optimized HD-TES does not significantly improve the stimulation focality at the ROIs. However, individually optimized TI does significantly improve the focality by up to ~4 cm for TI using two pairs of electrodes, and by up to ~1 cm for TI using two arrays of electrodes. This work demonstrates the need of individually optimizing TI to target deep brain areas, and advocates against using a common head model and montage for TI modeling and experimental studies.
Sexually selected traits predict female-biased philopatry in a sex-role reversed shorebird
Authors: Luna Leilton W. , Lipshutz Sara E.
Published: January 2025

Sex-biased dispersal plays a key role in shaping population dynamics and genetic structure. Two main hypotheses have been proposed for how territoriality and mating competition impact sex-biased dispersal. Female-biased dispersal is expected in monogamous systems with male resource defense, whereas male-biased dispersal is expected in polygynous systems with male competition over mates. However, patterns of sex-biased dispersal in polyandrous species, where females compete for both territories and mates, remain poorly understood. We investigated sex-biased dispersal in two polyandrous Jacana species, the Northern Jacana (Jacana spinosa) and Wattled Jacana (J. jacana), which exhibit intense female-female competition for territories and mates and differ in the strength of sexual selection. We analyzed sex-biased dispersal by assessing genetic differentiation and individual assignment indices in these jacana species across Central America. Our findings reveal strong male-biased dispersal in Northern Jacanas, indicated by higher genetic structuring and philopatry in females. In contrast, Wattled Jacanas showed no significant dispersal bias between sexes. Furthermore, sexually selected traits in Northern Jacana females, such as larger body mass, tarsus, and wing spur length, were associated with philopatry, suggesting that larger females retain territories, whereas smaller females disperse. To our knowledge, this is the first genetic evidence of male-biased dispersal in a polyandrous species. Our findings reveal that sexually selected traits, in addition to territorial and mate competition, are important for understanding species and sex differences in dispersal evolution.
Calcineurin-mediated regulation of GAP-43 is essential for neurite and synapse formation and protects against α-synuclein-induced degeneration
Authors: Zaichick Sofia , Grebenik Ekaterina , Caraveo Gabriela
Published: January 2025

Rise in calcium (Ca2+) and hyperactivation of Ca2+-dependent phosphatase calcineurin are two key determinants of α-synuclein (α-syn) pathobiology implicated in synucleinopathies such as Dementia with Lewy Bodies and Parkinson’s Disease. Calcineurin activity can be inhibited with FK506, a Food and Drug Administration (FDA)-approved compound. Our previous work demonstrated a protective effect of sub-saturating doses of FK506 against α-syn pathology in a rat model of α-syn neurodegeneration. This neuroprotection was associated with the phosphorylation of GAP-43. In this study, we present evidence that phosphorylation of GAP-43 regulated by calcineurin is a critical determinant for neurite branching and synapse formation. Phosphorylation of GAP-43 promotes neurite branching and synapse formation whereas dephosphorylation prevents it. Therefore, our findings provide a novel way in which GAP-43 activity can be regulated by calcineurin and provide the mechanistic basis for neuroprotection for FK506 effects in neurons experiencing α-syn proteotoxic stress.
Muscle Strength and Size Relationships with Unilateral Progressive Resistance Training
Authors: Deiwert Donald D. , Ma Sisi , Carey Christopher , Greenwell Davin , Gordish-Dressman Heather , Thompson Paul D. , Price Thomas , Angelopoulos Theodore J. , Clarkson Priscilla M. , Gordon Paul M. , Moyna Niall M. , Pescatello Linda S. , Visich Paul S. , Zoeller Robert F. , Hoffman Eric P. , Hubal Monica J.
Published: January 2025

Purpose

This study defines correlative and causal relationships between muscle strength and size before and after unilateral resistance training (RT) in a large cohort of healthy adults, focusing on sex differences within these relationships.

Methods

Results from 1233 participants (504 males and 729 females) in a retrospective analysis were included. Maximal voluntary isometric contraction strength (MVC), one-repetition maximum strength (1RM), biceps cross-sectional area (CSA) and elbow flexor volume (VOL) measures of the non-dominant and dominant arm were evaluated from baseline and after 12-wk RT twice per week. Correlations of MVC and VOL and 1RM and VOL were calculated in the whole cohort and within each sex independently. Causal analysis modeling was used to infer mechanistic relationships among variables.

Results

Absolute muscle strength and size related to one another both at baseline and following training, however correlation strength in each sex were weak. After RT, MVC relative change and VOL relative change correlations were correlated for the whole cohort (r=0.16; p<0.001) and females (r=0.18; p<0.001), but not in males (r=0.11; p=0.07). No significant correlations for relative change in 1RM and VOL were observed for the whole cohort or within sex. Causal discovery determined that change in VOL caused significant change in 1RM (but not MVC) and age was identified as a potential cause.

Conclusions

Sex differences occur in muscle size and strength relationship adaptations following resistance training, most notably the absence of significant relationships between relative size and strength changes in men. Simpson’s paradox bias, where assessing the combined data of males and females (also affecting overall sample size) affects identifies patterns differently than assessing relationships within each sex, may partially explain our findings.
New Cardiovascular Medications: Surveying Adoption Trends Among Cardiologists
Authors: Varjabedian Leon , Mohammadi Abbas , Mohammadi Ashkan , Vaseghi Yasaman
Published: January 2025

Introduction

This study investigates factors influencing the adoption of new cardiovascular medications by private practice cardiologists in Las Vegas, focusing on economic, clinical, and informational barriers. Understanding these challenges is critical for improving medication uptake and optimizing patient care.

Methods

A cross-sectional survey was conducted between January 1 and February 1, 2024, targeting private practice cardiologists in Las Vegas. Out of 47 invited participants, 68% completed the questionnaire. The survey evaluated economic barriers, patient considerations, and preferred methods of learning about new treatments.

Results

The survey revealed that 54% of cardiologists adopt new medications within 2–6 months of approval, while fewer adopt them within 2 months or after 6–12 months. Economic barriers, particularly prior authorization requirements and high patient copays, were the most frequently reported challenges, surpassing concerns about clinical benefits or medication safety. Traditional conferences and professional society events emerged as the preferred sources of information for learning about new treatments, significantly outweighing reliance on digital platforms or pharmaceutical representatives.

Discussion

Economic factors, such as prior authorizations and copays, significantly delay the adoption of new cardiovascular medications. Cardiologists show a strong preference for formal educational resources, such as conferences and professional society events, over pharmaceutical outreach or digital platforms. Addressing these barriers requires streamlining administrative processes, reducing patient copays, and improving access to high-quality educational events. Collaboration between insurers, medical societies, and healthcare providers is essential to overcoming these obstacles and enhancing patient outcomes.
The oncogenic CCDC6-RET fusion product is a dual ATP and ADP-dependent kinase that functions viacis-phosphorylation
Authors: Martín-Hurtado Ana , Contreras Julia , Sánchez-Wandelmer Jana , Zarzuela Eduardo , Muñoz Inés G. , Muñoz Javier , Isasa Marta , Plaza-Menacho Iván
Published: January 2025

Gene fusions products involving protein kinases are known drivers in human cancers and actionable targets for personalized therapy, yet the structural and molecular determinants that control their function are largely unexplored. Here we show that a CCDC6-RET fusion product, a driver and therapeutic target in lung and thyroid cancers, is a highly active dimeric kinase in solution. Time-resolved mass spectrometry analysis together with a robust biochemical and biophysical characterization reveal that CCDC6-RET functions as a dual ATP- and ADP-dependent kinase able to bind both nucleotides and uses them as phosphoryl donors. We also identify a crosstalk between the c-terminal and the activation segments, uncovering a mutually exclusive dependency by the former on activation loop phospho-sites controlling both the processing and the catalytic activity of the fusion protein. Furthermore, we generated a 3D-assembly of a CCDC6-RET homodimer combining electron microscopy (EM) single particle, small-angle X-ray scattering (SAXS) and in silico structural analyses. Our structural model together with cross-linking mass spectrometry data demonstrated that CCDC6-RET forms a face-to-facetrans-inhibited dimer in the apo state characterized by intermolecular-crosslinked activation segments. Upon nucleotide binding and catalytic domains reorientation, fast activation loop phosphorylation is driven by a mechanismin cis. Our work uncover for the first time the molecular and structural determinants that controls CCDC6-RET function and provides a solid framework to study the structure and function of other RET fusion products.