bluuebunny/crossref_metadata_2025 huggingface dataset:
Change in retinal perfusion with aflibercept for central retinal vein occlusion: the two-year prospective observational HERMES study
Authors: Glacet-Bernard Agnès , Girmens Jean-François , Coscas Florence , Nghiem-Buffet Sylvia , Morel Christophe , Erginay Ali , Weber Michel , Wang Xavier , Jung Camille , Cohen Salomon-Yves , Aubert Tristan , Blanco-Garavito Rocio , Souied Eric H , Miere Alexandra
Published: February 2025

Purpose:

To analyze retinal perfusion (RP) using ultrawide-field fluorescein angiography (UWFA) and optical coherence tomography angiography (OCTA), in patients with central retinal vein occlusion (CRVO) treated by intravitreal injection of aflibercept.

Methods:

Single-arm, multicenter, prospective, observational study. Treatment-naive eyes with CRVO initiated therapy with aflibercept. UWFA with correction of projection distortion and OCTA were performed at baseline (M0), M3, M12, and M24.

Results:

Fifty-six eyes were included. Visual acuity improved by 16 ETDRS letters at M12 (p<0.001), while mean central subfield thickness decreased from 801µm at M0 to 352µm at M12 (p<0.001). The ischemic index on UWFA increased from 17% at M0 to 23% at M3, and to 36% at M24. Ischemic CRVO accounted for 18% at M0, 25% at M3, and 39% at M24 (p<0.05). Vascular leakage was only present in 21% of eyes at M12. The density of the superficial and deep capillary plexus remained stable, but the foveal avascular zone enlarged from 0.37 mm2 at M0 to 0.61 mm2 at M24 (p=0.02). No cases of reperfusion were observed. The mean number of injections at M12 was 7.0±3.6.

Conclusion:

Changes in RP were characterized by worsening perfusion in the periphery, while macular capillaries maintained a generally stable density at M24, even in ischemic CRVO. These findings support the need for regular monitoring of peripheral retinal perfusion in treated patients to detect silent progression of nonperfusion, which may lead to neovascular complications, while visual acuity is maintained over the long term, likely due to the preserved macular capillary density.
Enormous Bilateral Optic Disc Drusen Presenting as a Central Retinal Vein and Cilioretinal Artery Occlusion
Authors: Naderi Amirreza , Spaide Richard
Published: February 2025

Purpose:

To report a case of combined cilioretinal artery and central retinal vein occlusion in a patient with extremely large, asymptomatic optic disc drusen.

Methods:

A patient with sudden vision loss underwent a comprehensive examination, including multimodal imaging.

Results:

A 45-year-old man with no previous visual symptoms presented with a combined cilioretinal artery and central retinal vein occlusion in the right eye. The optic nerve in the right eye was slightly hyperemic and the nerve appeared normal in the left eye. His optic nerves did not have a nodular appearance but showed subtle hyperautofluorescence. A hematological and clotting work-up was unrevealing. Optical coherence tomography revealed an exceptionally large, deeply embedded optic disc druse (1604 x 1390 μm) that almost spanned the width of the optic canal, starting from 464 μm beneath the optic disc surface extending to below any visible lamina cribrosa. The right eye demonstrated a paracentral scotoma, while a minimal visual field defect was observed in the left eye despite the presence of a large-sized (1125 x 803 μm) druse.

Conclusion:

While optic disc drusen are typically small nodular aggregates in the prelaminar optic nerve head, this patient had an enormous buried solitary druse of the optic nerve in each eye. The unexpected size and location of the drusen, along with the lack of preceding symptoms, suggest that they may not be detected in routine evaluations, thus necessitating multimodal imaging. The redundancy of nerve fibers in the optic nerve may allow significant asymptomatic damage prior to vascular occlusion.
Presumed Mitomycin C-Induced Retinal Toxicity Following Combined Cataract and Xen Gel Stent Surgery
Authors: Tuttle Jared. J. , Scarboro Shannon D. , Fitzpatrick John C. , Harper C. Armitage
Published: February 2025

Purpose:

To describe a case of presumed MMC-induced retinal toxicity following combined cataract and Xen gel stent surgery.

Methods:

Observational case report.

Results:

A 66-year-old male presents with progressive vision loss (20/25 baseline to light-perception (LP)) following combined cataract and Xen gel stent surgery in the left eye. The patient received 0.15 ml of 0.4 mg/ml of MMC via intra-tenon injection during the surgery. The patient reported severe eye pain following surgery which gradually resolved over time. Upon examination at post-operative day 41, vessel attenuation, sclerotic vessels, and optic nerve pallor are observed without any retinal hemorrhaging. At post-operative day 55, visual acuity remains at LP with a flat line electroretinogram. Outcomes remain consistent at postoperative day 125.

Conclusion:

Care should be taken to avoid intraocular MMC, especially when administered via intra-tenon injection during combined cataract and Xen gel stent surgery.
A case of Bartonella Neuroretinitis Presenting with Concomitant Frosted Branch Angiitis on long-term follow-up
Authors: Zhang Wenjing , Chen Cong , Song Yanping , Yan Ming
Published: February 2025

Purpose:

To report a patient with Bartonella henselae-associated ocular inflammation that manifested with central retinal vein occlusion and neuroretinitis.

Methods:

A case report including multimodal imaging and indirect fluorescent antibody test results was used.

Results:

This case highlights the importance of clinical examination and maintaining a high diagnostic suspicion for neuroretinitis in a healthy young woman without vascular risk factors.

Conclusion:

Patients with B. henselae-associated ocular inflammation develop retinal vein occlusion. For young patients with central retinal vein occlusion and neuroretinitis who do not have a history of systemic diseases, a detailed medical history should be taken and potential causes should be investigated.
Infusion-Induced Macular Holes in Pars Plana Vitrectomy: A Case Series of Six Patients
Authors: Shuman Hannah , Trivedi Vichar , Patwa Dhir , Lee Patrick SY , Tran David V , Im Jacob , Me Rao , Komro Jack , Okeagu Chinwenwa , Le Kim , Lin Xihui
Published: February 2025

Purpose:

To describe a series of six cases in which iatrogenic macular holes were induced by the infusion fluid flow of a 25-gauge pars plana vitrectomy (PPV) system.

Methods:

This is a retrospective case series of six patients treated at Kresge Eye Institute between 2018 and 2024.

Results:

Iatrogenic macular holes caused by infusion fluid flow are a rare complication of PPV. In this series, five out of six patients had a history of diabetes mellitus and proliferative diabetic retinopathy. The majority of these patients were undergoing repair of tractional retinal detachments when the complication occurred. The average patient age was 47 years (range: 32–66 years). Four patients were pseudophakic, and only one had undergone prior vitrectomy. Preoperative visual acuity ranged from 20/50 to hand motion, while postoperative visual acuity ranged from 20/80 to hand motion. Two patients experienced an improvement in visual acuity postoperatively.

Conclusion:

This case series highlights the potential risk of macular hole formation due to infusion fluid dynamics during pars plana vitrectomy. In diabetic patients with tractional retinal detachments or significant macular ischemia, we recommend positioning the infusion cannula away from the posterior pole to mitigate the risk of this complication.
Novel Software Program to Improve Biometry Measurements Obtained by an Optical Low Coherence Reflectometry Biometer
Authors: Cooke David L. , Cooke Tim L. , Patel Raj , Heath Michael T. , Gardiner Mason , Murphy David A. , Riaz Kamran M.
Published: February 2025

Purpose:

To evaluate a novel software program (SpikeFinder) that improves quality of measurements obtained by optical low coherence reflectometry (OLCR) biometry (Lenstar)

Setting:

Tertiary care academic center

Design:

Retrospective case series

Method

ology: After applying inclusion criteria, 12,988 eyes scanned with OLCR biometry and swept-source OCT (SS-OCT) biometry (IOLMaster700) were analyzed. Measurements, including axial length (AL), anterior chamber depth (ACD), and lens thickness (LT), were compared. SpikeFinder was applied to eyes with the most prominent ACD and LT measurement differences. Statistical testing was performed using Wilcoxon (two variables) and Kruskal-Wallis ANOVA tests (multiple variables) with Tukey post-hoc adjustments. Heteroscedastic testing (WHWK Statistics Package) was used to assess differences after software application.

Results:

99.1% of AL measurements were within 0.01 mm between the two biometers. SS-OCT LT was significantly longer than the OLCR LT: 33% differed by ≥ 0.50 mm (p<0.001). Correspondingly, SS-OCT ACD was significantly shorter than OLCR ACD: 14% differed by ≥ 0.50 mm (p<0.001). SS-OCT biometer – OLCR biometer values for ACD and LT before applying SpikeFinder were -0.64 ± 0.31 mm and 1.15 ± 0.38 mm, respectively (p<0.001). After applying SpikeFinder to a subgroup of 337 eyes, these differences were -0.02 ± 0.03 mm and 0.01 ± 0.11 mm, respectively. SpikeFinder ACD and LT values were similar to SS-OCT biometer-measured ACD (p=0.872) and LT (p=0.987) values.

Conclusion:

The SpikeFinder program can help improve the accuracy of ACD and LT measurements obtained by the OLCR biometer, which may enhance the performance of formulas that utilize these measurements.
In vivo capsular bag size in children with congenital cataract: Implications for placement of Intraocular Lens
Authors: Sukhija Jaspreet , Kaur Savleen , Gupta Kajree , Kumari Kiran , Sethi Sameer ,   Advanced Eye Centre
Published: February 2025

Purpose:

To measure the equatorial lens diameter in vivo and correlate it with other biometric variables in children undergoing cataract surgery.

Setting:

Tertiary care institution

Design:

Prospective case series

Methods:

Children < 5 years with cataracts were included. Those with corneal opacities, previous ocular surgery, traumatic cataracts, and or any coexisting corneal or retinal ocular pathology were excluded.In addition to routine investigations, all patients underwent Ultrasound biomicroscopy (UBM) of both eyes. Correlation between the measured value of axial length, corneal diameter, age, and bag diameters and their effect on Intraocular Lens (IOL) implantation (Aphakia/Pseudophakia) were observed.

Results:

We included 112 eyes of 68 children with a mean age of 11.42 + 11.34 months ( 1 month - 4 years). Mean capsular bag diameter(CBD) in the eyes where IOL was placed successfully in the bag was 8.27 ± 0.6 mm (7.1 – 9.39 mm). The eyes in which IOL placement was difficult in the bag and who were either left aphakic or bicapsular capture IOL was performed had a mean diameter of 7.09 ±0.99 mm (5.23 – 9.09 mm) (p<0.05). A significant and positive correlation was found between CBD and age, axial length, and corneal diameter (p=0.00; 0.00; 0.001 and r=0.4,0.4 and 0.8, respectively). Bag diameter had the highest association(odds ratio 4) with successful IOL placement

Conclusions:

Bag diameters should be measured preoperatively in children with cataracts along with other biometric variables as it is the most important measurement that helps in making a decision regarding implantation and positioning of IOL.
International Physician Assistant Exchange: Facilitating Kinship in Education and Patient Care
Authors: Hopkins Aislinn , Chillura Christopher , Durham Isabell , Fowler Madelyn , Merritt Kaitlin , Schilling Taylor
Published: February 2025

The international exchange of physician assistant (PA) education between the Medical University of South Carolina (MUSC) in the United States and Inholland University in the Netherlands, established in 2013, aims to enhance global awareness, cultural sensitivity, and professional development among PA students. This exchange program, which transitioned to a virtual format during the COVID-19 pandemic and resumed in-person exchanges in 2023, allows participants to explore similarities and differences in medical education, healthcare systems, and professional practices between the two countries. Despite varying educational pathways and healthcare models, the role of PAs in both countries shows remarkable similarities, including shared responsibilities in patient care and clinical practice flexibility. The program, which includes lectures, clinical shadowing, and cultural immersion, fosters a deeper understanding of global healthcare and promotes introspection among participants regarding their own healthcare systems. Student reflections highlight the transformative impact of the exchange on their cultural humility and global perspective. Future plans for the program include enhanced virtual interactions to strengthen cross-cultural connections and further explore healthcare topics. This exchange serves as a model for fostering international collaboration and broadening the global PA community.
The Intent of the Physician’s Order for Life-Sustaining Treatment
Authors: Meyer Jeannette (Jeannie)
Published: February 2025

Portable Medical Orders (PMO) such as the Physician’s Order for Life-Sustaining Treatment and the Medical Order for Life-Sustaining Treatment have proven to be valuable documents that allow patients who are medically frail or have life-limiting illnesses to communicate their health care wishes. Because these documents are in the form of a Physician’s Order that can travel across multiple health care settings, they offer a form of certainty and reassurance for the patient that their wishes will be respected. The PMO depends on a conversation between the trained health care provider and the patient or their designee. The PMO functions as a legal document, communicating medical orders that must be followed and providing clinicians who do so with legal protection. The choices within (including resuscitation, treatment choices, and artificial feeding) must be understood by the patient in association with their own prognosis and health care status; the signatures within the form attest that a discussion of those choices has taken place and the patient understands not only their choices, but also the implications of them. A PMO with incomplete signatures is not a valid legal document. In the scenario presented here, the author discusses a scenario in which the discussions did not take place and the signatures are questionable, leading the patient to receive aggressive medical treatment that might not be in their best interests. The reasons behind the above ethical issues are related to a misconception and misuse of the PMO within a long-term care facility. Unfortunately, as noted in the literature cited and in the author’s own experience, these ethical issues are not uncommon.
Multimodality Imaging Characteristics of Radiographically Occult Giant Cell Tumor of the Ilium: Insights From 18F-FDG PET/CT, Bone Scintigraphy, X-ray, and MRI
Authors: Huang Juncheng , Loi Hoi Yin
Published: February 2025

We report a case of a 38-year-old man with lower back pain. Initial radiographs revealed a radiographically occult lytic lesion in the right ilium. MRI showed a heterogeneously enhancing mass with fluid-fluid levels, while 18F-FDG PET-CT revealed an FDG-avid lesion, suspicious for malignancy. Bone scintigraphy indicated a “doughnut” sign, and the biopsy showed features supportive of a giant cell tumor. Giant cell tumor, a primary bone tumor rarely found in the ilium, can potentially be radiographically occult and may pose a diagnostic dilemma on PET/CT. Incorporating multimodality imaging (such as bone scintigraphy) with pathologic findings may facilitate earlier intervention with denosumab therapy, for favorable outcomes.
Nonlinear Relationship Between the C-Reactive Protein to Albumin Ratio and Chronic Kidney Disease: A Cross-Sectional Analysis Using the NHANES Database
Authors: Huang Quanyuan , Lu Xiao , Liang Yuanhua , Zhu Wuchang , Chen Jinglan , Yang Yufang
Published: February 2025

Objective

The C-reactive protein to albumin ratio (CAR) has gained attention as an inflammatory biomarker with potential relevance in various diseases. However, its relationship with chronic kidney disease (CKD) remains inadequately understood. This study aims to investigate the association between CAR and CKD prevalence in a diverse, multi-ethnic U.S. cohort.

Methods

This cross-sectional analysis utilized data from the 1999–2010 National Health and Nutrition Examination Survey (NHANES). Multivariable regression and subgroup analyses were conducted to control for confounding factors and examine the link between CAR and CKD. A restrictive cubic spline model was employed to explore potential nonlinear associations.

Results

Among 30,049 participants aged 18 years or older, 5,423 (18.05%) had CKD. Compared to the lowest quartile (Q1) of log-transformed CAR, CKD risk was higher in the second (Q2), third (Q3), and fourth (Q4) quartiles, with odds ratios of 1.28, 1.29, and 1.63, respectively. A dose-response relationship was observed, indicating that higher CAR levels were significantly associated with increased CKD risk.

Conclusion

Elevated CAR is independently associated with a higher prevalence of CKD, suggesting its potential utility as a biomarker for CKD risk assessment in diverse populations. Further studies are needed to confirm these findings and explore underlying mechanisms.
YAbS: The Antibody Society’s antibody therapeutics database
Authors: Rawat Puneet , Crescioli Silvia , Prabakaran R. , Sharma Divya , Greiff Victor , Reichert Janice M.
Published: February 2025

Therapeutic antibodies have gained prominence in recent years due to their precision in targeting specific diseases. As these molecules become increasingly essential in modern medicine, comprehensive data tracking and analysis are critical for advancing research and ensuring successful clinical outcomes. YAbS, The Antibody Society’s Antibody Therapeutics Database, serves as a vital resource for monitoring the development and clinical progress of therapeutic antibodies. The database catalogues detailed information on over 2,900 commercially sponsored investigational antibody candidates that have entered clinical study since 2000, as well as all approved antibody therapeutics. Data for the late-stage clinical pipeline and antibody therapeutics in regulatory review or approved (over 450 molecules) are openly accessible (https://db.antibodysociety.org). Antibody-related information includes molecular format, targeted antigen, current development status, indications studied, and the clinical development timeline of the antibodies, as well as the geographical region of company sponsors. Furthermore, the database supports in-depth industry trends analysis, facilitating the identification of innovative developments and the assessment of success rates within the field. This resource is continually updated and refined, providing invaluable insights to researchers, clinicians, and industry professionals engaged in antibody therapeutics development.
Integrative Multi-Omics Framework for Causal Gene Discovery in Long COVID
Authors: Pinero Sindy , Li Xiaomei , Liu Lin , Li Jiuyong , Lee Sang Hong , Winter Marnie , Nguyen Thin , Zhang Junpeng , Le Thuc Duy
Published: February 2025

Background

Long COVID, or Post-Acute Sequelae of COVID-19 (PASC), involves persistent, multisystemic symptoms in about 10–20% of COVID-19 patients. Although age, sex, ethnicity, and comorbidities are recognized as risk factors, identifying genetic contributors is essential for developing targeted therapies.

Methods

We developed a multi-omics framework using Transcriptome-Wide Mendelian Randomization (TWMR) and Control Theory (CT). This approach integrates Expression Quantitative Trait Loci (eQTL), Genome-Wide Association Studies (GWAS), RNA sequencing (RNA-seq), and Protein-Protein Interaction (PPI) networks to detect causal genes and regulatory nodes that drive critical expression changes in Long COVID.

Results

We identified 32 causal genes (19 previously reported and 13 novel), which act as regulatory drivers influencing disease risk, progression, and stability. Enrichment analyses highlighted pathways linked to the SARS-CoV-2 response, viral carcinogenesis, cell cycle regulation, and immune function. Analysis of other pathophysiological conditions revealed shared genetic factors across syndromic, metabolic, autoimmune, and connective tissue disorders. Using these genes, we identified three distinct symptom-based subtypes of Long COVID, offering insights for more precise diagnosis and potential therapeutic interventions. Additionally, we provided an open-source Shiny application to enable further data exploration.

Conclusion

Integrating TWMR and CT revealed genetic mechanisms and therapeutic targets for Long COVID, with novel genes informing pathogenesis and precision medicine strategies.
Immune imprinting and vaccination interval underly XBB.1.5 monovalent vaccine immunogenicity
Authors: Wrynla Xammy H. , Bates Timothy A. , Trank-Greene Mila , Wahedi Mastura , Hinchliff Audrey , Curlin Marcel E. , Tafesse Fikadu G.
Published: February 2025

As COVID-19 transitions into endemicity and vaccines are annually updated to circulating SARS-CoV-2 lineages such as JN.1, exposure intervals and immune imprinting become critical considerations for vaccination strategy. Imprinting by the ancestral spike protein has been observed with the bivalent Wuhan-Hu-1/BA.4-5 vaccine and its persistence can be further evaluated in the context of the more recent XBB.1.5 monovalent vaccine. We assessed antibody responses in individuals who received three to four doses of Wuhan-Hu-1, one dose of bivalent Wuhan-Hu-1/BA.4-5, and one dose of XBB.1.5 vaccine (bivalent recipients). We compared these to individuals who received three to four doses of Wuhan-Hu-1 and one dose of XBB.1.5 vaccine without prior bivalent vaccination (bivalent non-recipients). Before XBB.1.5 vaccination, bivalent non-recipients demonstrated decreased breadth and potency of neutralizing antibodies compared to recipients, but at post-vaccination exhibited greater boosting of neutralizing antibodies against XBB.1.5 (18.4X versus 6.2X), EG.5.1 (30.9X versus 7.0X), and JN.1 (9.2X versus 3.7X) variants with trends toward higher neutralizing titers and comparable variant cross-neutralization. Increased boosting in non-recipients were similarly observed for IgA and total IgG/A/M isotypes binding the spike receptor-binding domain but not IgG nor IgM. Bivalent non-recipients had longer intervals between exposures, which has been reported to enhance antibody boosting; however, bivalent receipt and interval were tightly linked variables, preventing the isolation of individual contributions to boosting. Nonetheless, significant “back-boosting” of ancestral SARS-CoV-2 titers upon XBB.1.5 vaccination in both participant groups indicate that immune imprinting continues to affect contemporary vaccines. Altogether, our findings highlight imprinting and exposure intervals as important phenomena underlying variant-adapted COVID-19 vaccine immunogenicity.
Interplay between cytokine and FGF2 signaling in induction of entosis and vasculogenic mimicry response in glioblastoma
Authors: Kang Tae-Yun , Park JinSeok , Dincer Alper , Baskaran Janani , Ren Chunxiao , Scuderi Soraya , Yang Liang , McGuone Declan , Miller-Jensen Kathryn , Günel Jennifer Moliterno , Günel Murat , Levchenko Andre
Published: February 2025

Tumor vascularization is critical to survival of cancer cells, but is frequently perturbed leading to disorganized angiogenesis and emergence of alternative means of delivery of oxygen and nutrients, such as vasculogenic mimicry (VM). Understanding of VM and its relationship to endothelial vascularization has been hampered by the lack of comprehensive combination ofin vivoclinical data and relevantin vitromodels. We address this challenge by analyzing glioblastoma (GBM) tumors and clinically isolated cancer cells. This analysis strongly suggests a key role of macrophage-induced controlled cell death in emergence of VM. The results further point to entosis of cancer cells as a critical intermediate state in this process, enabled by mechano-chemical cell heterogeneity. We find evidence that macrophages can regulate endothelial angiogenesis and VM as two alternative vascularization mechanisms. These results reveal mechanistic underpinnings of VM and pave the way to predictive analysis of tumor progression.
Sex Specific Attenuation of Reward Preference
Authors: Turner Christopher A. , Becker Jill B.
Published: February 2025

Estradiol receptor signaling has a sex-specific impact on the brain’s reward pathways, enhancing cocaine reinforcement in females but not in males. Selective activation of G-Protein Coupled Estradiol Receptor 1 (GPER-1) in the dorsolateral striatum (DLS) attenuates the reinforcing effects of 0.1% saccharin (SACC) and cocaine in males but not females. This study investigated GPER-1 activation in the DLS and systemically using the GPER-1 agonist, G1, to assess its effect on SACC and cocaine preference in male and female rats. Five experiments were conducted using gonad-intact and gonadectomized animals to determine dose-response effects and the influence of circulating hormones. Intra-DLS GPER-1 activation with 20% G1 selectively reduced SACC preference in intact males but not females, while higher and lower concentrations had no effect. Systemic G1 administration attenuated cocaine-induced conditioned place preference (CPP) in both sexes in a dose-dependent way. Interestingly, systemic administration of G1 did not alter SACC preference in either sex, regardless of the presence or absence of gonadal hormones. These findings suggest that GPER-1 activation influences reward processing in a site, reward, and sex-dependent manner.

Highlights

Selective activation of the membrane-associated estradiol receptor, GPER-1, in the dorsolateral striatum (DLS) attenuates preference for a 0.1% saccharin solution (SACC) in male but not female rats.

Systemic activation of the membrane-associated estradiol receptor, GPER-1, attenuates cocaine-induced condition place preference (CPP) in both males and females in a dose-dependent way.

Systemic GPER-1 activation does not influence SACC preference in either sex.
A lateralized pathway for associating nutrients with flavors
Authors: Grove James C. R. , Li Queenie , Backes Heiko , Kuzmanovic Bojana , Choi Jaewon , Ubadiah Violeta , Qiu Longhui , Zhang Jingkun , Liu Zhengya , Small Dana M. , Tittgemeyer Marc , Knight Zachary A.
Published: February 2025

Animals learn about the external world, in part, via interoceptive signals1,2. For example, the nutrient content of food is first estimated in the mouth, in the form of flavor, and then measured again via slower signals from the gut. How these signals from the mouth and gut are integrated to drive learning is unknown. Here we identify a lateralized dopamine pathway that is specialized for learning about the nutrient content of food. We show that dopamine neurons in the ventral tegmental area (VTADA) are necessary for associating nutrients with flavors, but that this does not involve canonical dopamine targets in the striatum. Instead, post-ingestive nutrients trigger DA release selectively in a small region of the anterior basolateral amygdala (BLA). Remarkably, this hotspot for nutrient-triggered DA release is localized to the left side of the brain in both mice and humans, revealing that the DA system is lateralized. We identify the gut sensors that are responsible for nutrient-triggered DA release; show that they selectively activate BLA-projecting DA neurons defined by expression of cholecystokinin (CCK); and demonstrate that stimulation of DA axon terminals in the anterior BLA drives flavor-nutrient learning but not other aspects of behavior. Two-photon imaging of neurons in the left anterior BLA reveals that they encode food flavors, and these representations are strengthened by post-ingestive nutrients, whereas silencing of these neurons prevents flavor-nutrient learning. These findings establish a neural basis for how animals learn about the nutrient content of their food. They also reveal unexpectedly that post-ingestive nutrients are differentially represented on the right and left sides of the brain.
The Global Status of Global Surgery Indicators: A Scoping Review Protocol
Authors: Hyman Gabriella Y. , Kratky Lauren , Reddy Ramya , Bain Paul A. , Raykar Nakul P.
Published: February 2025

Background

Surgical care is essential to achieving health system goals, including Universal Health Coverage (UHC) and the Sustainable Development Goals (SDGs). The Lancet Commission on Global Surgery (LCoGS) proposed core indicators to assess surgical system capacity, delivery, and financial risk protection. Despite their importance, variability and inconsistent reporting limit their utility in tracking progress toward Global Surgery 2030.

Aims

This review aims to quantify the status of five global surgery indicators globally, describe current indicator reporting practices, and identify facilitators and barriers to regular indicator reporting, providing recommendations to improve future tracking and policy implementation.

Methods

Following the Joanna Briggs Institute (JBI) and PRISMA-ScR guidelines, we will search peer-reviewed databases and grey literature to identify studies reporting LCoGS indicators. Data extraction will focus on indicator status, reporting frequency, and associated challenges. Results will be analyzed quantitatively and thematically.

Conclusion

By mapping current indicator reporting, this review will provide actionable insights to inform future policy, improve data collection practices, and accelerate progress toward achieving Global Surgery 2030 targets.
Restoring STAR*D: A Reanalysis of Drug-Switch Therapy After Failed SSRI Treatment Using Patient-Level Data with Fidelity to the Original STAR*D Research Protocol
Authors: Xu Colin , Kim Thomas T. , Kirsch Irving , Plöderl Martin , Amsterdam Jay D. , Pigott H. Edmund
Published: February 2025

Background

TheSequenced Treatment Alternatives to Relieve Depression(STAR*D) trial was designed to give guidance in selecting the best next-step treatment for depressed patients who did not remit during their first, and/or subsequent, antidepressant trial, with up to four trials per patient. Our prior research documented protocol violations which inflated STAR*D’s reported cumulative remission rate by 91.4%. A similar reanalysis of the step-2 drug-switch trial has not been done until now.

Methods

We reanalyzed the patient-level dataset of STAR*D’s drug-switch treatment therapies—with fidelity to the original research protocol and related publications—to determine whether there were clinically-relevant differences in results compared to the original publication.

Results

While our reanalysis largely comported with STAR*D’s published findings of no significant differences between drug-switch treatments, we found the following discrepancies: Lower than reported step-2 remission rates ranging from 16.2 to 19.3% (versus 17.6 to 24.8%); A significant increase in treatment-emergent suicidal ideation during the step-2 drug-switch therapies ranging from 11.2 to 15.0% compared to step-1 citalopram treatment (9.0%); A four times greater number of severe suicidal behaviors reported by the treating clinicians compared to the published suicide-related Serious Adverse Events (16 versus 4); and A sustained remission rate of only 3.1 to 8.4%.

Conclusion

Compared to the original publication, our reanalysis found lower remission rates and more suicidal risk than reported. This adds to the discrepancies found in our prior reanalysis and also to the finding that switching antidepressants is not well supported by the evidence.
The effect of population selection criteria on model estimates and data missingness in electronic health record studies
Authors: Pritchard Emma , Vihta Karina-Doris , Pouwels Koen B. , Lipworth Samuel , Hope Russell , Muller-Pebody Berit , Quan T. Phuong , Cregan Jack , Hopkins Susan , Eyre David W. , Walker A. Sarah
Published: February 2025

Objective

Electronic Health Records (EHRs) provide information to explore those at risk of various diseases, though studying entire populations is limited by data availability, potentially introducing biases. We compared different samples, varied by type of hospital contact, to assess the impact on missing data and model results.

Materials and Methods

UsingEscherichia colibloodstream infections as a case study, we used data from Oxfordshire, UK, containing individuals with hospital contact, including blood tests from primary care providers. We compared two approaches: an “inpatient sample” requiring previous/current inpatient contact, reducing missing risk factors but restricting the denominator, and a broader “healthcare contact sample”, defined by previous healthcare contact (including outpatient appointments, emergency department visits, community blood tests), maximising inclusion.

Results

The healthcare contact sample contained more missing data for key demographics and systematically missing data for potential risk factors including diagnosis codes. Missing data was more common in controls than cases (17–21% controls missing vital signs versus 6–7% cases [inpatient sample]) but varied little with lookback duration. Model estimates showed small, insubstantial shifts between the samples. Compared to population estimates, younger males were unrepresented, while those aged≥75y were largely captured.

Discussion

Including individuals with any previous healthcare contact resulted in more missing data versus restricting to inpatient-only contact. Despite this, there were only small shifts in model estimates. There were large but expected differences between EHR samples and population-level data.

Conclusion

Different sample selection approaches for EHR analyses could impact power and associations. Ideally, multiple approaches should be compared.
Self-supervised image restoration in coherent X-ray neuronal microscopy
Authors: Laugros Alfred , Cloetens Peter , Bosch Carles , Schoonhoven Richard , Pavlovic Liam , Kuan Aaron T. , Livingstone Jayde , Zhang Yuxin , Kim Minsu , Hendriksen Allard , Holler Mirko , Wanner Adrian A. , Azevedo Anthony , Batenburg K. Joost , Tuthill John C. , Lee Wei-Chung Allen , Schaefer Andreas T. , Vigano Nicola , Pacureanu Alexandra
Published: February 2025

Coherent X-ray microscopy is emerging as a transformative technology for neuronal imaging, with the potential to offer a scalable solution for reconstruction of neural circuits in millimeter sized tissue volumes. Specifically, X-ray holographic nanoto-mography (XNH) brings together outstanding capabilities in terms of contrast, spatial resolution and data acquisition speed. While recent XNH developments already enabled generating valuable datasets for neuro-sciences, a major challenge for reconstruction of neural circuits remained overcoming resolving power limits to distinguish smaller neurites and synapses in the reconstructed volumes. Here we present a self-supervised image restoration approach that simultaneously improves spatial resolution, contrast, and data acquisition speed. This enables revealing synapses with XNH, marking a major milestone in the quest for generating connectomes of full mammalian brains. We demonstrate that this method is effective for various types of neuronal tissues and acquisition schemes. We propose a scalable implementation compatible with multi-terabyte image volumes. Altogether, this work brings large-scale X-ray nanotomography to a new precision level.
Identifying regulators of aged fibroblast activation in 3D tissue models
Authors: Liu Hui , Yuan Luezhen , Shivashankar G.V.
Published: February 2025

Robust 3D tissue culture models to activate aged fibroblasts for cell-based therapies and identify regulators of such activation are still missing. In our previous study, we showed that aged fibroblasts can be activated simply through applying compressive force, without the need for exogenous factors, leading to increased migration. In this study, we develop a pipeline to evaluate the role of specific pharmacological inhibitors for transcription factor inference and cell migration involved in aged fibroblast activation. By integrating RNA-seq data with bioinformatic tools (prize collecting Steiner tree method and iRegulon) we inferred 15 candidates. In addition, we used cell migration and heterochromatin content as readouts for validating these candidates. Furthermore, we identified three potential master regulators of fibroblast activation and rejuvenation: FOXO1, STAT3, and PDK1. These findings offer valuable insights for future drug discovery, disease modeling, and regenerative medicine.
Tracing social mechanisms and interregional connections in Early Bronze Age Societies in Lower Austria
Authors: Furtwängler Anja , Rebay-Salisbury Katharina , Neumann Gunnar , Kanz Fabian , Ringbauer Harald , Bianco Raffaela , Schmidt Tanja , Semerau Lena , Radzeviciute Rita , Barquera Rodrigo , Rohland Nadin , Stewardson Kristin , Workman J. Noah , Curtis Elizabeth , Zalzala Fatma , Callan Kim , Iliev Lora , Qiu Lijun , Cheronet Olivia , Wagner Anna , Morante Guillermo Bravo , Spannagel Michaela , Teschler-Nicola Maria , Novotny Friederike , Verdianu Domnika , Pinhasi Ron , Reich David , Krause Johannes , Stockhammer Philipp W. , Mittnik Alissa
Published: February 2025

In this study, we present the results of archaeogenetic investigations of Early Bronze Age individuals from Lower Austria, specifically associated with the Únětice and Unterwölbling cultural groups. Through analysing newly generated genome-wide data of 138 individuals, we explore the social structure and genetic relationships within and between these communities. Our results reveal a predominantly patrilocal society with non-strict female exogamic practices. Additionally, Identity-by-Descent (IBD) analysis detects long-distance genetic connections, emphasizing the complex network of interactions in Central Europe during this period. Despite shared social dynamics, notable genetic distinctions emerge between the Únětice and Unterwölbling groups. These insights contribute to our understanding of Bronze Age population interconnections and call for a nuanced interpretation of social dynamics in this historical context.
Rigid Control of Motor Unit Firing Rates in the Human Tibialis Anterior Muscle Persists during Neurofeedback
Authors: Lee Meng-Jung , Ofner Patrick , Huang Hsien-Yung , Mulder Joris , Ibanez Jaime , Farina Dario , Mehring Carsten
Published: February 2025

The conventional framework of motor-unit (MU) control assumes that MUs in a MU pool are constrained by a fixed recruitment order and a common input. This rigid-control framework has been challenged by recent findings suggesting that MU activity could be flexibly modulated, potentially mediated by descending cortical inputs. In this study, rather than evaluating flexibility from the perspective of recruitment thresholds, we investigated control flexibility by assessing if human participants can voluntarily modulate MU firing rates beyond rigid-control constraints. Specifically, we examined whether participants could voluntarily modulate the firing rates of a pair of MUs from the tibialis anterior muscle during real-time feedback. Two tasks involving target-reach with different visual feedback derived from the MUs firing rates were conducted. In both tasks, there was no evidence that participants were able to change MU firing rates in a way that would violate rigid control robustly. Our findings demonstrate limited flexibility in MU control in human tibialis anterior muscle within single-session training, even when real-time MU activity feedback was provided. The results suggest that MU flexibility is not inherently present in the human lower limb.
Ketamine Alters Tuning of Neural and Behavioral Spatial Working Memory Precision
Authors: Rahmati Masih , Moujaes Flora , Suljič Nina Purg , Ji Jie Lisa , Berkovitch Lucie , Lee Kangjoo , Fonteneau Clara , Schleifer Charles H. , Adkinson Brendan D. , Savič Aleksandar , Santamauro Nicole , Tamayo Zailyn , Diehl Caroline , Kolobaric Antonija , Flynn Morgan , Camarro Terry , Curtis Clayton E. , Repovš Grega , Fineberg Sarah K. , Morgan Peter T. , Preller Katrin H. , Krystal John H. , Murray John D. , Cho Youngsun T. , Anticevic Alan
Published: February 2025

Deficits in working memory (WM) are a hallmark of neuropsy-chiatric disorders such as schizophrenia, yet their neurobiological basis remains poorly understood. GlutamateN-methyl-D-aspartate receptors (NMDARs) are critical for spatial WM (sWM), with NMDAR antagonist ketamine known to attenuate task-evoked activation and reduce sWM accuracy. Cortical microcircuit models hypothesize that NMDAR antagonism impairs sWM by broadening neural spatial tuning, but this mechanism has not been directly tested in humans. Using a pharmacological fMRI approach, we showed how ketamine broadened neural spatial tuning, attenuated activation across visual, parietal, and frontal areas, and worsened sWM performance in healthy humans. Ketamine-induced changes in tuning were more consistent across individuals and brain regions than changes in overall activation and correlated with individual differences in sWM performance. These findings provide empirical evidence linking NMDAR antagonism to disruptions in cortical microcircuit dynamics, the resulting neural tuning alterations, and sWM impairments, advancing frameworks for therapeutic development.
Dopaminergic mechanisms of dynamical social specialization in mouse microsocieties
Authors: Solié C. , Nicolson A. , Justo R. , Layadi Y. , Morin B. , Batifol C. , Reynolds LM , Le Borgne T. , Fayad SL , Gulmez A. , Allegret--Vautrot J. , de Chaumont F. , Viollet C. , Didienne S. , Debray N. , Hardelin J-P. , Girard B. , Mourot A. , Naudé J. , Marti F. , Delord B. , Faure P.
Published: February 2025

Social organization and division of labor are fundamental to animal societies, but how do these structures emerge from individual interactions, and what role does neuromodulation play in shaping them? Using behavioral tracking in a semi-natural environment, neural recordings, and computational models integrating reinforcement and social learning, we show that groups of three isogenic mice spontaneously develop specialized roles while solving a foraging task requiring individual decisions under social constraints. Moreover, these roles are shaped by dopaminergic activity in the ventral tegmental area. Strikingly, despite minor sex-differences in behavior when mice were tested alone, male triads formed stable worker-scrounger relationships driven by competition, whereas female triads adopted uniform, cooperative strategies. Model analysis revealed how intra- and inter-sex parameter differences in resource exploitation, combined with contingent and dynamic social interactions, drive behavioral specialization and labor division. Most notably, it highlighted how contingency, amplified by competition, magnifies individual differences and shapes social profiles. The plastic, adaptive nature of social organization within triads was confirmed by manipulating dopaminergic cell activity, which reshaped social roles and altered group structure. Our findings support a feedback loop where social context shapes neural states, which in turn reinforce behavioral specialization and stabilize social structures.
Whole genome sequencing reveals how plasticity and genetic differentiation underlie sympatric morphs of Arctic charr
Authors: Kurta Khrystyna , Fedi Mariano Olivera , Baker Kendall , Barker Tom , Catchpole Leah , Ciofi Claudio , Cocco Arianna , Diedericks Genevieve , Diroma Maria Angela , Hindar Kjetil , Iannucci Alessio , Irish Naomi , Knitlhoffer Vanda , Laikre Linda , Leitão Henrique G. , Lucchini Sacha , McTaggart Seanna , Pálsson Arnar , Pettersson Mats E. , Ryman Nils , Snorrason Sigurður S. , Svardal Hannes , Swarbreck David , Waterhouse Robert M. , Watkins Christopher , Xiao Han H. , Gharbi Karim , Jónsson Zophonías O. , Andersson Leif
Published: February 2025

Salmonids have a remarkable ability to form sympatric morphs after postglacial colonization of freshwater lakes. These morphs often exhibit differences in morphology, feeding, and spawning behaviour. Here we explore the genetics of morph differentiation by establishing a high-quality, annotated reference genome for the Arctic charr and use this as a resource for population genomic analysis of morphs from two Norwegian and two Icelandic lakes. The four lakes represent the spectrum of genetic differentiation between morphs from one lake with no genetic differentiation between morphs, implying phenotypic plasticity only, to two lakes with locus-specific genetic differentiation, implying incomplete reproductive isolation, and one lake with strong genome-wide divergence consistent with complete reproductive isolation. As many as 12 putative inversions ranging from 0.45 to 3.25 Mbp in size segregated among the four morphs present in one lake, Thingvallavatn, and these contributed significantly to the genetic differentiation among morphs. None of the putative inversions was found in any of the other lakes, but there were cases of partial haplotype sharing in similar morph contrasts in other lakes. The results are consistent with a highly polygenic basis of morph differentiation with limited genetic parallelism between lakes. The results support a model where morph differentiation is usually first established due to phenotypic plasticity that results in niche expansion and separation, followed by gradual development of reproductive isolation and locus-specific differentiation and eventually complete reproductive isolation and genome-wide divergence. A major explanation for salmonids ability to diversify into multiple sympatric morphs is likely the genome complexity caused by their ancient whole genome duplication that enhances evolvability.
MicroSplit: Semantic Unmixing of Fluorescent Microscopy Data
Authors: Ashesh Ashesh , Carrara Federico , Zubarev Igor , Galinova Vera , Croft Melisande , Pezzotti Melissa , Gong Daozheng , Casagrande Francesca , Colombo Elisa , Giussani Stefania , Restelli Elena , Cammarota Eugenia , Battagliotti Juan Manuel , Klena Nikolai , Di Sante Moises , Pigino Gaia , Taverna Elena , Harschnitz Oliver , Maghelli Nicola , Scherer Norbert F. , Dalle Nogare Damian Edward , Dechamps Joran , Pasqualini Francesco , Jug Florian
Published: February 2025

Fluorescence microscopy, a key driver for progress in the life sciences, faces limitations due to the microscope's optics, fluorophore chemistry, and photon exposure limits, necessitating trade-offs in imaging speed, resolution, and depth. Here, we introduce MicroSplit, a computational multiplexing technique based on deep learning that allows multiple cellular structures to be imaged in a single fluorescent channel and then unmix them by computational means, allowing faster imaging and reduced photon exposure. We show that MicroSplit efficiently separates up to four superimposed noisy structures into distinct denoised fluorescent image channels. Furthermore, using Variational Splitting Encoder-Decoder (VSE) networks, our approach can sample diverse predictions from a trained posterior of solutions. The diversity of these samples scales with the uncertainty in a given input, allowing us to estimate the true prediction errors by computing the variability between posterior samples. We demonstrate the robustness of MicroSplit across various datasets and noise levels and show its utility to image more, to image faster, and to improve downstream analysis. We provide MicroSplit along with all associated training and evaluation datasets as open resources, enabling life scientists to immediately benefit from the potential of computational multiplexing and thus help accelerate the rate of their scientific discovery process.