bluuebunny/crossref_metadata_2025 huggingface dataset:
Pattern of admission, outcome and predictors of trauma patients visiting the surgical emergency department in comprehensive specialized hospital: a retrospective follow-up study
Authors: Zegeye Robel Mesfin , Nigatu Yonas Addisu , Fentie Demeke Yilkal , Arefayne Nurhusen Riskey , Tegegne Biresaw Ayen
Published: April 2024

Background:

Traumatic injuries represent a huge burden in the developing world, and a significant proportion has found in low-income and middle-income countries. However, the pattern, outcome and factors of injury varies from setup to setup and is less studied in public health problems.

Objective:

To assess pattern of admission, outcome and its predictors among trauma patients visiting the surgical emergency department in a comprehensive specialized hospital.

Methods:

A retrospective follow-up study was conducted, and data were taken from the medical records of patients from 2019 to 2021. A simple random sampling technique was used to get a sample size of 386 from injured patient charts. Data were entered into Epi-Data version 4.6 software and exported to STATA version 14.1 for analysis. The dependent variable was injured patient’s outcome, which could be died or not died. The independent variables with P value less than 0.25 in the bi-variable regression analysis were considered for the multivariable regression. Adjusted odds ratio (AOR) with the 95% CI were used to declare statistical significance.

Result:

About 13.99% of injured patients with (95% CI: 10, 17) had died during the study period. The leading cause of injury was assault (62.44%) followed by road traffic accidents (26.17%). Severe Glasgow Coma Scale (AOR 6.6; 95% CI: 2.6–16.4), length of hospital stay more than or equal to 7 days (AOR=2.8; 95% CI: 1.2–6.2), time of arrival in between 1 and 24 h (AOR=0.15; 95% CI: 0.06–0.37), and upper trunk injury (AOR=6.3; 95% CI: 1.3–28.5) were significantly associated with mortality.

Conclusion and recommendation:

Mortality after traumatic injury was considerably high. Severe Glasgow Coma Scale, Length of hospital stay more than or equal to 7 days, time of arrival in between 1 and 24 h, and upper trunk injury were the associated factors for mortality. Priority should be given for injured patients with decreased levels of consciousness and upper trunk injury. The establishment of organized pre-hospital emergency services and provision of timely arrival is recommended. The authors recommend prospective follow-up study.
Assessing the Reliability of Facial Feminization Content on Social Media and Its Impact on the Dissemination of Misinformation
Authors: Hauc Sacha C. , Mehrzad Raman , Rivera Jean C. , Hanrahan Grace B. , de Baun Heloise M. , Cruz Claudia A. , Woo Albert S.
Published: April 2024

Background

The surge in social media usage has transformed the dissemination and consumption of healthcare information, notably impacting plastic surgery and cosmetic specialties. This study focuses on the influence of social media, particularly Instagram and TikTok, in shaping perceptions of individuals seeking facial feminization (FF) procedures.

Methods

Using the validated DISCERN scale, we assessed the reliability and accuracy of FF content on TikTok and Instagram. The study also analyzed the relationship between content reliability on engagement metrics (likes, comments, views) and the type of content shared (educational, testimonial, promotional).

Results

The analysis encompassed 225 TikTok videos and 75 Instagram posts. TikTok content showed 9.33% as “very poor,” 66.2% as “poor,” 22.6% as “fair,” and only 1.33% as “excellent.” Similarly, Instagram content demonstrated 14.67% as “very poor” and 69.33% as “poor,” with no content rated as “good” or “excellent.” Educational content received higher reliability scores on both platforms. TikTok engagement metrics showed lower reliability ratings correlating with more views, comments, and likes.

Conclusion

The study underscores the critical role of social media in shaping patient perspectives on FF procedures. The prevalence of inaccurate information necessitates a focus on responsible engagement by healthcare professionals, aiming to provide accurate, educational content that aligns with patients' informational needs and ultimately enhances surgical outcomes.
Repair of Sciatic Nerve Defect in Rats With Acellular Nerve Allograft Carrying Vascular Endothelial Cells
Authors: Meng Dehua , Xu Qintong , Chen Zenggan , Pan Jianfeng , Jiang Libo , Zou Jiapeng , Yuan Yaqin , Zhang Jian , Lineaweaver William C. , Zhang Feng
Published: April 2024

Background

Acellular nerve allografts (ANAs) were developed to replace the autologous nerve grafts (ANGs) to fill the peripheral nerve defects. Poor vascularization relative to ANGs has been a limitation of application of ANAs.

Methods

A total of 60 female Sprague-Dawley rats were assigned 3 groups. The rats in A group received ANGs, the rats in B group received ANAs, and the rats in C group were transplanted with ANA carrying endothelial cells (ANA + ECs). In the 1st, 2nd, 4th, and 12th postoperative weeks, 5 rats were selected from each group for evaluating sciatic function index (SFI), electrophysiology, maximum tetanic force recovery rate, tibialis anterior muscle weights recovery rate, and microvessel density. In the 12th postoperative week, the nerves were harvested and stained with toluidine blue and observed under an electron microscope to compare nerve fibers, myelin width, and G-ratio.

Results

All the rats survived. In the first and second postoperative weeks, more microvessels were found in the ANA + EC group. In the 12th postoperative week, the nerve fibers were more numerous, and G-ratio was smaller in the C group compared with the B group. The compound muscle action potential and maximum tetanic force recovery rate in the tibialis anterior muscle in the C group were better than those in the B group in the 12th postoperative week. The A group showed better performances in electrophysiology, maximum tetanic force, muscle wet weight, and nerve regeneration.

Conclusion

ANA + ECs can promote early angiogenesis, promoting nerve regeneration and neurological function recovery.
Application of Crus of Helix Incision Through the Posterior Parotid Gland Approach in the Mid-Level or High-Level Mandibular Condylar Fractures
Authors: Liu Xiang , Shao Shengjie , Lou Huiquan , Xia Yichao
Published: April 2024

Objective:

This study is to explore the clinical effect of crus of helix incision through the posterior parotid gland approach in the treatment of Mid-or High-Level mandibular condylar fractures.

Methods:

From September 2020 to June 2023, we performed incision reduction internal fixation of 23 patients with mid-level or high-level fractures of the mandibular condylar through the approach of the posterior parotid gland, and observed the effect of the operation.

Results:

After a follow-up period of 6 to 12 months, all patients showed no signs of postoperative facial paralysis or salivary gland fistula. In addition, satisfactory scars were observed in the operation area, and the occlusion function had recovered well.

Conclusion:

The approach of using a crus of helix incision through the posterior parotid gland proved to be an effective method for treating mid-level or high-level fractures of the condylar fractures. This technique offers several advantages, including adequate exposure, minimal facial nerve injury, ease of incision and reduction, inconspicuous scarring, and a more concealed incision.
Antecedent Cardiac Arrest Status of Donation After Circulatory Determination of Death (DCDD) Kidney Donors and the Risk of Delayed Graft Function After Kidney Transplantation: A Cohort Study
Authors: Philipoff Adam , Lin Yingxin , Teixeira-Pinto Armando , Gately Ryan , Craig Jonathan C. , Opdam Helen , Chapman Jeremy C. , Pleass Henry , Rogers Natasha M. , Davies Christopher E. , McDonald Stephen , Yang Jean , Lopez Pedro , Wong Germaine , Lim Wai H.
Published: April 2024

Background.

The number of donors from donation after circulatory determination of death (DCDD) has increased by at least 4-fold over the past decade. This study evaluated the association between the antecedent cardiac arrest status of controlled DCDD donors and the risk of delayed graft function (DGF).

Methods.

Using data from the Australia and New Zealand Dialysis and Transplant, the associations between antecedent cardiac arrest status of DCDD donors before withdrawal of cardiorespiratory support, DGF, posttransplant estimated glomerular filtration rate (eGFR), and allograft loss were examined using adjusted logistic, linear mixed modeling, and cox regression, respectively. Among donors who experienced cardiac arrest, we evaluated the association between duration and unwitnessed status of arrest and DGF.

Results.

A total of 1173 kidney transplant recipients received DCDD kidneys from 646 donors in Australia between 2014 and 2019. Of these, 335 DCDD had antecedent cardiac arrest. Compared with recipients of kidneys from donors without antecedent cardiac arrest, the adjusted odds ratio (95% confidence interval) for DGF was 0.85 (0.65-1.11) among those with kidneys from donors with cardiac arrest. There was no association between antecedent cardiac arrest and posttransplant eGFR or allograft loss. The duration of cardiac arrest and unwitnessed status were not associated with DGF.

Conclusions.

This focused analysis in an Australian population showed that the allograft outcomes were similar whether DCDD donors had experienced a prior cardiac arrest, with no associations between duration or unwitnessed status of arrest and risk of DGF. This study thus provides important reassurance to transplant programs and the patients they counsel, to accept kidneys from donors through the DCDD pathway irrespective of a prior cardiac arrest.
Characterization of Chronic Graft-versus-host Disease After Haploidentical Stem Cell Transplantation With Posttransplant Cyclophosphamide: A Study on Behalf of GETH-TC
Authors: Fonseca-Santos Marta , Bailen Rebeca , Lopez-Godino Oriana , Herruzo-Delgado Beatriz , Bermudez Maria Aranzazu , García-Cadenas Irene , Huguet-Mas María , Ferra-Coll Christelle , Esquirol Albert , Cortés-Rodriguez María , Yañez-Sansegundo Lucrecia , Pascual-Cascon Maria Jesus , Heras Inmaculada , Kwon Mi , Lopez-Corral Lucía ,   on behalf of Grupo Español de Trasplante Hematopoyético y Terapia Celular
Published: April 2024

Background.

Chronic graft-versus-host disease (cGVHD) is a cause of late morbidity and nonrelapse mortality (NRM) after allogenic hematopoietic stem cell transplantation (allo-HSCT). Although studies evaluating haploidentical allo-HSCT (haplo-HSCT) using posttransplant cyclophosphamide (PTCy) demonstrate lower cGVHD rates, comprehensive data describing the clinical profile, risk factors, or outcomes of cGVHD within this platform are scarce.

Methods.

We conducted a retrospective multicenter analysis of 389 consecutive patients who underwent haplo-HSCT PTCy in 7 transplant centers of the Spanish Group Grupo Español de Trasplante Hematopoyético y Terapia Celular (GETH-TC) between 2008 and 2020 describing incidence, clinical profile, risk factors, and cGVHD outcomes.

Results.

Ninety-five patients of 389 developed cGVHD. Our data revealed that the incidence and severity of cGVHD are lower than those reported for HLA-identical transplantation with conventional prophylaxis and that the strongest predictor for cGVHD was previous acute GVHD (P = 0.031). Also, recipient age ≥60 y (P = 0.044) was protective against cGVHD. Moreover, patients with moderate cGVHD had longer event-free survival at 3 y than other patients (P = 0.016) and a lower relapse rate at 3 y (P = 0.036).

Conclusions.

Our results support the fact that the incidence and severity of cGVHD are lower than those reported for HLA-identical transplantation with conventional prophylaxis. In this series, patients who develop moderate cGVHD after haplo-HSCT PTCy had a higher overall survival and event-free survival, and lower relapse, suggesting higher graft-versus-leukemia effect. Although this is the largest series focused on characterizing cGVHD in haplo-HSCT PTCy, further prospective studies are needed to confirm the findings.
Effectiveness of the 2023-2024 Formulation of the Coronavirus Disease 2019 mRNA Vaccine against the JN.1 Variant
Authors: Shrestha Nabin K. , Burke Patrick C. , Nowacki Amy S. , Gordon Steven M.
Published: April 2024

Background

The purpose of this study was to evaluate whether the 2023-2024 formulation of the COVID-19 mRNA vaccine protects against COVID-19 caused by the JN.1 lineage of SARS-CoV-2.

Methods

Employees of Cleveland Clinic in employment when the JN.1 lineage of SARS-CoV2 became the dominant circulating strain, were included. Cumulative incidence of COVID-19 was examined prospectively. Protection provided by vaccination (analyzed as a time-dependent covariate) was evaluated using Cox proportional hazards regression. The analysis was adjusted for the propensity to get tested, age, sex, pandemic phase when the last prior COVID-19 episode occurred, and the number of prior vaccine doses.

Results

Among 47561 employees, COVID-19 occurred in 838 (1.8%) during the 16-week study period. In multivariable analysis, the 2023-2024 formula vaccinated state was associated with a significantly lower risk of COVID-19 while the JN.1 lineage was the dominant circulating strain (hazard ratio [HR], .77; 95% confidence interval [C.I.], .62-.94;P= .01), yielding an estimated vaccine effectiveness of 23% (95% C.I., 6%-38%). Compared to 0 or 1 prior vaccine doses, risk of COVID-19 was incrementally higher with 2 prior doses (HR, 1.46; 95% C.I., 1.12-1.90;P< .005), 3 prior doses (HR, 1.95; 95% C.I., 1.51-2.52;P< .001), and more than 3 prior doses (HR, 2.51; 95% C.I., 1.91-3.31;P< .001).

Conclusions

The 2023-2024 formula COVID-19 vaccine given to working-aged adults afforded a low level of protection against the JN.1 lineage of SARS-CoV-2, but a higher number of prior vaccine doses was associated with a higher risk of COVID-19.

Among 47561 working-aged Cleveland Clinic employees, the 2023-2024 formula COVID-19 vaccine was 23% effective against the JN.1 lineage of SARS-CoV-2, but a higher number of prior COVID-19 vaccine doses was associated with a higher risk of COVID-19.
Cardiovascular damage in parents of patients with mucopolysaccharidoses
Authors: Nguyen T.L. , Reznik E.V. , Semyachkina A.N. , Voinova V.Yu. , Shkolnikova M.A.
Published: April 2024

Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases. Cardiovascular pathology occurs in all types of MPS, represented by valvular defects, myocardial hypertrophy, and coronary artery disease. Cardiovascular abnormalities in parents of carriers with MPS are poorly understood, which was the purpose of our work.

In 2022 year 21 parents (81% female) of children with MPS were examined.The median (25th and 75th percentiles) of age was 36 (33; 37) years. All MPS carriers-parents underwent a standard clinical and laboratory examination, ECG, echocardiography, 24-hour Holter ECG monitoring.

There were no confirmed myocardial and brain infarctions, diabetes mellitus in the examined carriers. Arterial hypertension was diagnosed in 14.3% of carriers. A decrease in LV ejection fraction <40% was found in 4.8%, up to 40-50% in 9.5% of carriers. LV wall thickness ≥1.5 cm was detected in 66.7% of carriers, asymmetric LVH in 85.7%. Thickening of the mitral valve leaflets (MV) was detected in 76.2% of carriers. Hydropericardium was detected in 23.8% of carriers. Atrial fibrillation was registered in 4.8%, atrial flutter - in 4.8%, paroxysmal supraventricular tachycardia - in 33.3%, sinus bradycardia - in 14.3%; conduction disorders - in 71.4% of carriers. A short PR interval was detected on the ECG 9.5% of carriers. A prolonged QT interval was registered in 14.3% of carriers, transient ST-segment depression in 47.6%, ST-segment elevation in 14.3% of carriers.

Our results suggest the possibility of clinical manifestations of cardiac involvement in MPS carriers.
Integrative multi-omics characterization of hepatocellular carcinoma in Hispanic patients
Authors: Das Debodipta , Wang Xiaojing , Chiu Yu-Chiao , Bouamar Hakim , Sharkey Francis E. , Lopera Jorge E. , Lai Zhao , Weintraub Susan T. , Han Xianlin , Zou Yi , Chen Hung-I H. , Zeballos Torrez Carla R. , Gu Xiang , Cserhati Matyas , Michalek Joel E. , Halff Glenn A. , Chen Yidong , Zheng Siyuan , Cigarroa Francisco G. , Sun Lu-Zhe
Published: April 2024

Background

The incidence and mortality rates of hepatocellular carcinoma (HCC) among Hispanics in the United States are much higher than those of non-Hispanic whites. We conducted comprehensive multi-omics analyses to understand molecular alterations in HCC among Hispanic patients.

Methods

Paired tumor and adjacent non-tumor samples were collected from 31 Hispanic HCC in South Texas (STX-Hispanic) for genomic, transcriptomic, proteomic, and metabolomic profiling. Additionally, serum lipids were profiled in 40 Hispanic and non-Hispanic patients with or without clinically diagnosed HCC.

Results

Exome sequencing revealed high mutation frequencies ofAXIN2andCTNNB1in STX Hispanic HCCs, suggesting a predominant activation of the Wnt/β-catenin pathway. TheTERTpromoter mutation frequency was also remarkably high in the Hispanic cohort. Cell cycles and liver functions were identified as positively- and negatively-enriched, respectively, with gene set enrichment analysis. Gene sets representing specific liver metabolic pathways were associated with dysregulation of corresponding metabolites. Negative enrichment of liver adipogenesis and lipid metabolism corroborated with a significant reduction in most lipids in the serum samples of HCC patients. Two HCC subtypes from our Hispanic cohort were identified and validated with the TCGA liver cancer cohort. The subtype with better overall survival showed higher activity of immune and angiogenesis signatures, and lower activity of liver function-related gene signatures. It also had higher levels of immune checkpoint and immune exhaustion markers.

Conclusions

Our study revealed some specific molecular features of Hispanic HCC and potential biomarkers for therapeutic management of HCC and provides a unique resource for studying Hispanic HCC.
Potent neutralization by a receptor binding domain monoclonal antibody with broad specificity for SARS-CoV-2 JN.1 and other variants
Authors: Piepenbrink Michael S. , Khalil Ahmed Magdy , Chang Ana , Mostafa Ahmed , Basu Madhubanti , Sarkar Sanghita , Panjwani Simran , Ha Yaelyn H. , Ma Yao , Ye Chengjin , Wang Qian , Green Todd J. , Kizziah James L. , Erdmann Nathaniel B. , Goepfert Paul A. , Liu Lihong , Ho David D. , Martinez-Sobrido Luis , Walter Mark R. , Kobie James J.
Published: April 2024

SARS-CoV-2 continues to be a public health burden, driven in-part by its continued antigenic diversification and resulting emergence of new variants. While increasing herd immunity, current vaccines, and therapeutics have improved outcomes for some; prophylactic and treatment interventions that are not compromised by viral evolution of the Spike protein are still needed. Using a rationally designed SARS-CoV-2 Receptor Binding Domain (RBD) – ACE2 fusion protein and differential selection process with native Omicron RBD protein, we developed a recombinant human monoclonal antibody (hmAb) from a convalescent individual following SARS-CoV-2 Omicron infection. The resulting hmAb, 1301B7 potently neutralized a wide range of SARS-CoV-2 variants including the original Wuhan and more recent Omicron JN.1 strain, as well as SARS-CoV. Structure determination of the SARS-CoV-2 EG5.1 Spike/1301B7 Fab complex by cryo-electron microscopy at 3.1Å resolution demonstrates 1301B7 contacts the ACE2 binding site of RBD exclusively through its VH1-69 heavy chain, making contacts using CDRs1-3, as well as framework region 3 (FR3). Broad specificity is achieved through 1301B7 binding to many conserved residues of Omicron variants including Y501 and H505. Consistent with its extensive binding epitope, 1301B7 is able to potently diminish viral burden in the upper and lower respiratory tract and protect mice from challenge with Omicron XBB1.5 and Omicron JN.1 viruses. These results suggest 1301B7 has broad potential to prevent or treat clinical SARS-CoV-2 infections and to guide development of RBD-based universal SARS-CoV-2 prophylactic vaccines and therapeutic approaches.
Lowering The Acoustic Noise Burden in MRI with Predictive Noise Canceling
Authors: Šiurytė Paulina , Weingärtner Sebastian
Published: April 2024

Even though Magnetic Resonance Imaging (MRI) exams are performed up to 16 times per every 100 inhabitants each year, patient comfort and acceptance rates are strongly compromised by exposure to loud acoustic noise. Here we present a system for acoustic noise cancellation using anti-noise derived from predicted scanner sounds. In this approach, termed predictive noise canceling (PNC), the acoustic fingerprint of an MRI system is obtained during a 60 s calibration, and used to predict anti-noise for arbitrary scan procedures. PNC achieves acoustic noise attenuation of up to 13 dB across a wide range of clinical MRI sequences, with spectral noise peak reduction of up to 96.76 % occurring between 0.6 and 1.2 kHz. These results suggest that predicted scanner noise can achieve substantial in-bore noise cancellation with the prospect of providing a cheap and scanner-independent solution for improved patient comfort.
GREMLIN1 disrupts intestinal epithelial-mesenchymal crosstalk to induce a wnt-dependent ectopic stem cell niche via stromal remodelling
Authors: Mulholland EJ. , Belnoue-Davis HL. , Valbuena GN. , Gunduz N. , Ligezal A. , Biswasl S. , Gil Vasquez E. , Omwengal S. , Nasreddinl N. , Hodder M. , Wang LM. , Irshad S. , Ng AS. , Jennings LK. , Midwood KS. , Dedi N. , Ridgeway R. , Phesse T. , East JE. , Tomlinson IPM. , Davies GCG. , Sansom O. , Leedham SJ.
Published: April 2024

In homeostasis, counterbalanced morphogen signalling gradients along the vertical axis of the intestinal mucosa regulate the fate and function of epithelial and stromal cell compartments. Here, we used a disease-positioned mouse, and human tissue, to explore the consequences of pathological Bone Morphogenetic Protein (BMP) signalling dysregulation on epithelial- mesenchymal interaction. Aberrant pan-epithelial expression of the secreted BMP antagonist GREM1, resulted in ectopic crypt formation with lineage tracing demonstrating the presence ofLgr5(-)stem/progenitor cells. Isolated epithelial cellGrem1expression had no effect on individual cell fate, indicating an intercompartmental impact of mucosal-wide BMP antagonism. Treatment with a novel anti-Grem1 antibody abrogated the polyposis phenotype, and triangulation of specific pathway inhibitors defined a pathological sequence of events, with wnt-ligand dependent ectopic stem cell niches formed through stromal remodelling following BMP disruption. These data support an emerging co-evolutionary model of intestinal cell compartmentalisation based on bidirectional regulation of epithelial-mesenchymal cell fate and function.

One Sentence Summary

Pathological epithelial GREM1 expression induces therapeutically reversible ectopic stem cell niches through stromal remodelling
Learning Discriminative Representations of Superimposed P waves With Weakly-Supervised Temporal Contrastive Learning
Authors: Hejc Jakub , Redina Richard , Pospisil David , Rakova Ivana , Kolarova Jana , Starek Zdenek
Published: April 2024

Electrocardiography (ECG) wave morphology and timing provide critical information for diagnosing arrhythmias and conduction abnormalities, allowing risk stratification for various cardiac diseases. However, extraction of these features becomes challenging in the presence of superimposed waves from distinct cardiac chambers, a common occurrence during pathological rhythms. This work proposes a novel Surrogate-boosted Temporal Contrastive Representation Learning (S-TCRL) frame-work to address this challenge. S-TCRL leverages weak labels, readily obtainable from invasive catheter examinations, to extract latent representations of superimposed P waves.

We reformulate the problem from object-wise to sample-wise incomplete information by employing surrogate labels. A 1D fully-convolutional feature pyramid network (FPN) extracts multi-scale features from ECG signals. These features are segmented into equal-sized temporal regions, whose labels are inferred from individual samples using a multiple-instance learning (MIL) paradigm. Non-sequential embeddings are generated to facilitate alignment-free cosine similarity estimation. A temperature-scaled cross-entropy loss function minimizes the distance between embeddings of similar regions (likely containing P waves) while maximizing the distance between dissimilar ones.

The framework’s efficacy is evaluated on a custom ECG dataset comprising 3265 short-term recordings from 708 individuals undergoing catheter ablation. S-TCRL achieves significant improvement in the downstream P wave segmentation task compared to two baseline MIL methods. The average re-call and precision for both P wave boundaries reach 70.0% and 80.0%, respectively, exceeding the base-lines’ 63.5% and 67.5%. The results demonstrate the potential of S-TCRL for embedding representation of superimposed P waves and its generalizability to tasks such as arrhythmia classification.
Enhancement of spatial learning by 40 Hz visual stimulation requires parvalbumin interneuron-dependent hippocampal neurogenesis
Authors: Yan Hai , Deng Xufan , Wang Yunxuan , Wu Shiyu , Du Jun , Yu Mei , Liu Bo , Wang Huimei , Pan Yifan , Zhang Zhengyu , Chen Jinghong , Wang Yizheng , Walker Tara , Bartlett Perry , Ju Jun , Hou Sheng-Tao
Published: April 2024

Acute and short-term rhythmic 40 Hz light flicker stimulation has shown promising results in alleviating cognitive impairments in mouse models of Alzheimer’s disease (AD), stroke, and autism spectrum disorders (ASD). Understanding the long-term impacts and underlying mechanisms is crucial to progress this approach for potential human therapeutic applications. Here, we show that prolonged exposure to 40 Hz light flicker (1 hour per day for 30 days) significantly improved spatial learning and neurogenesis in the dentate gyrus (DG) without harmful behavioral side effects. Mice with transgenic deletion of doublecortin-positive cells (DCXDTR) in the adult hippocampus failed to exhibit enhanced neurogenesis and spatial learning with 40 Hz stimulation. Inactivation or knockout of GABAergic parvalbumin (PV) interneurons reduced the effects of 40 Hz entrainment and neurogenesis enhancement. Mechanistically, the stimulation did not alter the regional microvessel blood flow but significantly raised PV excitability and GABA levels and enhanced inhibitory transmission in the DG. Blocking GABAAreceptors reversed the improvements in spatial learning and neurogenesis. These data showed that long-term exposure to 40 Hz light flicker enhances spatial learning through PV-dependent adult neurogenesis, which requires elevated GABA as a critical neurochemical mechanism for sustaining adult neurogenesis.

In brief

Rhythmic 40 Hz light flicker alleviates cognitive impairments in diverse animal models of neurological diseases. Understanding its long-term effects and mechanisms is vital for advancing its therapeutic potential for humans. Here, we show that prolonged exposure to this flicker improves spatial learning and boosts adult neurogenesis in the dentate gyrus. Activation of PV interneurons and GABAergic support for the newborn immature neurons underlie this effect, demonstrating lasting benefits for the treatment of neurological diseases.

Highlights

Long-term exposure to 40 Hz light flicker significantly improved spatial learning and neurogenesis in the hippocampus, devoid of adverse effects.

The 40 Hz light flicker evoked adult neurogenesis requires the activity of GABAergic inhibitory PV interneurons.

The 40 Hz light flicker raised GABA levels and enhanced inhibitory transmission in the DG.

Increased GABA serves as a vital neurochemical mechanism to support adult neurogenesis.
Curved light sheet microscopy for centimeter-scale cleared tissues imaging
Authors: Tang Lijuan , Wang Jiayu , Ding Jiayi , Sun Junyou , Chen Xing-jun , Shen Quqing , Song Ruiheng , Cao Peng , Gong Rong , Xu Fang , Ge Woo-ping , Sun Wenzhi , Zhao Hu , Wu Jianglai
Published: April 2024

Imaging large cleared tissues requires scaling the throughput of imaging techniques. Here we introduce curved light sheet microscope to perform optical sectioning with curved light sheets. This concept addresses the long-standing field curvature problem and lowers the barriers in designing high-throughput objectives. Leveraging a customized objective, the curved light sheet microscope achieves diffraction-limited resolution (1.0 μm laterally and 2.5 μm axially) and uniform contrast over a field of view of more than 1 × 1 cm2and is compatible with various tissue clearing techniques. Imaging an entire intact cleared mouse brain at 0.625 × 0.625 × 1.25 μm3voxel size takes less than 3 hours and image tiling is not required. We share full optics description of the objective and report imaging neuronal and vascular networks and tracing brain-wide long-distance axonal projections in intact mouse brains.
Genetic characterization of cucumber genetic resources in the NARO Genebank indicates their multiple dispersal trajectories to the East
Authors: Shigita Gentaro , Shimomura Koichiro , Tran Dung Phuong , Haque Naznin Pervin , Duong Thuy Thanh , Imoh Odirichi Nnennaya , Monden Yuki , Nishida Hidetaka , Tanaka Katsunori , Sugiyama Mitsuhiro , Kawazu Yoichi , Tomooka Norihiko , Kato Kenji
Published: April 2024

The cucumber (Cucumis sativus) is an economically important vegetable crop cultivated and consumed worldwide. Despite its popularity, the manner in which cucumbers were dispersed from their origin in South Asia to the rest of the world, particularly to the east, remains a mystery due to the lack of written records. In this study, we performed genotyping-by-sequencing (GBS) on 723 worldwide cucumber accessions, mainly deposited in the Japanese National Agriculture and Food Research Organization (NARO) Genebank, to characterize their genetic diversity, relationships, and population structure. Analyses based on over 60,000 genome-wide single-nucleotide polymorphisms identified by GBS revealed clear genetic differentiation between Southeast and East Asian populations, suggesting that they reached their respective region independently, not progressively. A deeper investigation of the East Asian population identified two subpopulations with different fruit characteristics, supporting the traditional classification of East Asian cucumbers into two types thought to have been introduced by independent routes. Finally, we developed a core collection of 100 accessions representing at least 93.2% of the genetic diversity present in the entire collection. The genetic relationships and population structure, their associations with geographic distribution and phenotypic traits, and the core collection presented in this study are valuable resources for elucidating the dispersal history and promoting the efficient use and management of genetic resources for research and breeding in cucumber.
Proposed network of Marine Protected Areas supports larval dispersal and connectivity in the Eastern Mediterranean
Authors: Berenshtein Igal , Stern Nir , Tagar Aviyam , Paris Claire B. , Lapidot Omri , Morov Arseniy R. , Fredj Erick , Zaken Jacob , Biton Eli
Published: April 2024

The marine environment of the Eastern Mediterranean is under growing threat due to natural and anthropogenic stressors. Networks of Marine Protected Areas (MPAs) are effective tools in protecting marine environments and conserving their biodiversity. Currently, only 4% of the Israeli territorial waters are declared as MPAs, however six new MPAs, which will encompass more than 20% of the Israeli territorial waters, are planned. A central component in the effectiveness of MPAs is the degree to which the protected populations are connected. The purpose of our study is performing a comprehensive connectivity analysis for the proposed network of MPAs. We find that the proposed network substantially supports local and regional larval connectivity patterns for five target species in terms of the number of recruits, betweenness centrality, as well as the number of regional and local MPAs connections. Overall, the results provide strong support for the efficiency of the proposed MPAs in facilitating local and regional larval connectivity. Our findings will be useful for marine spatial planning and natural resource management and will enhance the protection and conservation of our marine environment.
siRNADesign: A Graph Neural Network for siRNA Efficacy Prediction via Deep RNA Sequence Analysis
Authors: Long Rongzhuo , Guo Ziyu , Han Da , Yuan Xudong , Chen Guangyong , Heng Pheng-Ann , Zhang Liang
Published: April 2024

The clinical adoption of small interfering RNAs (siRNAs) has prompted the development of various computational strategies for siRNA design, from traditional data analysis to advanced machine learning techniques. However, previous studies have inadequately considered the full complexity of the siRNA silencing mechanism, neglecting critical elements such as siRNA positioning on mRNA, RNA base-pairing probabilities, and RNA-AGO2 interactions, thereby limiting the insight and accuracy of existing models. Here, we introducesiRNADesign, a Graph Neural Network (GNN) framework that leverages both non-empirical and empirical rules-based features of siRNA and mRNA to effectively capture the complex dynamics of gene silencing. In multiple internal datasets, siRNADesign achievesstate-of-the-artperformance. Significantly, siRNADesign also outperforms existing methodologies inin vitrowet lab experiments and an externally validated dataset. Additionally, we develop a new data-splitting methodology that addresses the data leakage issue, a frequently overlooked issue in previous studies, ensuring the robustness and stability of our model under various experimental settings. Through rigorous testing, siRNADesign has demonstrated remarkable predictive accuracy and robustness, making significant contributions to the field of gene silencing. Furthermore, our approach in redefining data-splitting standards aims to set new benchmarks for future research in the domain of predictive biological modeling for siRNA.
The enzyme glutamate-cysteine ligase (GCL) is a target for ferroptosis induction in cancer
Authors: Eaton John K. , Chatterji Priya , Furst Laura , Basak Sneha , Patel Ayesha M. , Sweat Yan Y. , Cai Luke L. , Dave Krishna , Victorio Rachelle A. , Pizzi Elizabeth , Noorbakhsh Javad , Tian Gaochao , Roth Jennifer A. , Hynes John , Xing Gang , Wawer Mathias J. , Viswanathan Vasanthi S.
Published: April 2024

Despite glutathione’s long-recognized role as a major cellular antioxidant and its central role in ferroptosis defense, inhibition of glutathione biosynthetic enzymes has received little attention as a target for the therapeutic induction of ferroptosis. Here, we report that small-molecule inhibition of glutamate–cysteine ligase (GCL), the rate-limiting enzyme of glutathione biosynthesis, selectively and potently kills cancer cells by ferroptosis. We further describe novel GCL inhibitors including KOJ-1 and KOJ-2, compounds with excellent cellular potency and pharmacological properties, representing valuable tools to study the biology of ferroptosis and glutathione.
Validation of ferroptosis in canine cancer cells to enable comparative oncology and translational medicine
Authors: Chatterji Priya , Xing Gang , Furst Laura , Dave Krishna , Zhou Qiong , LaBarbera Daniel V. , Thamm Douglas H. , Eaton John K. , Wawer Mathias J. , Viswanathan Vasanthi S.
Published: April 2024

Ferroptosis is a cell death mechanism that has attracted significant attention as a potential basis for the development of new cancer therapies. Validation of ferroptosis biology in species commonly used in translation and pre-clinical development is a necessary foundation for enabling the advancement of such ferroptosis modulating drugs. Here, we demonstrate that canine cancer cells exhibit sensitivity to a wide range of ferroptosis-inducing perturbations in a manner indistinguishable from human cancer cells, and recapitulate characteristic patterns of ferroptotic response across tumor types seen in the human setting. The foundation provided herein establishes the dog as a relevant efficacy and toxicology model for ferroptosis and creates new opportunities to leverage the canine comparative oncology paradigm to accelerate the development of ferroptosis-inducing drugs for human cancer patients.
Variant electrical activation and recovery in normal human hearts revealed by noninvasive electrocardiographic imaging
Authors: Stoks Job , Patel Kiran , van Rees Bianca , Nguyen Uyen Chau , Mihl Casper , Deissler Peter M , ter Bekke Rachel MA , Peeters Ralf , Vijgen Johan , Dendale Paul , Ng Fu , Cluitmans Matthijs JM , Volders Paul GA
Published: April 2024

Background and aims

Although electrical activity of the normal human heart is well-characterized by the 12-lead electrocardiogram, detailed insights into within-subject and between-subject variations of ventricular activation and recovery by noninvasive electroanatomic mapping are lacking. We characterized human epicardial activation and recovery within and between normal subjects using noninvasive electrocardiographic imaging (ECGI) as a basis to better understand pathology.

Methods

Epicardial activation and recovery were assessed by ECGI in 22 normal subjects, 4 subjects with bundle branch block (BBB) and 4 with long-QT syndrome (LQTS). We compared characteristics between the ventricles (LV versus RV), sexes and age groups (<50y/≥50y (years)). Pearson’s correlation coefficient (CC) was used for within-subject and between- subject comparisons.

Results

Age of normal subjects averaged 49±14 years, 6/22 were male, and no structural/electrical heart disease was present. Average activation time was longer in LV than in RV, but not different by sex or age. Electrical recovery was similar for the ventricles, but started earlier and was on average shorter in males than females. Median CCs of between-subject comparisons of the ECG signals, activation and recovery patterns were 0.61, 0.32 and 0.19, respectively. Within-subject beat-to-beat comparisons yielded higher CCs (0.98, 0.89 and 0.82, respectively). Activation and/or recovery patterns of patients with BBB or LQTS contrasted significantly with those found in the normal population.

Conclusion

Activation and recovery patterns vary profoundly between normal subjects, but are stable individually beat to beat, with a male preponderance to shorter recovery. Individual characterization by ECGI at baseline serves as reference to better understand the emergence, progression and treatment of electrical heart disease.

Graphical abstract

Central illustration.

Application of electrocardiographic imaging (ECGI) in healthy controls allows to study normal epicardial activation and recovery patterns. Top: Although all subjects had a normal ECG, we found that their underlying activation time (AT) and recovery time (RT) patterns could be profoundly different. Still, beat-to-beat AT and RT patterns within one subject were relatively similar. Bottom: On a population level, we found that average right-ventricular (RV) AT was lower than left-ventricular (LV) AT, and both first and average RT were lower in males than in females.
The prognostic, predictive and clinicopathological impact of KRT81 / HNF1A- and GATA6- based transcriptional subtyping in pancreatic cancer
Authors: Guenther Michael , Surendran Sai Agash , Heinemann Volker , Haas Michael , Boeck Stefan , Ormanns Steffen
Published: April 2024

BACKGROUND

Transcriptional subtypes of pancreatic ductal adenocarcinoma (PDAC) have prognostic implications and potential predictive functions. This study aimed to determine their clinicopathological impact in large cohorts of advanced and resected PDAC and their evolution during disease progression.

METHODS

The clinicopathological and prognostic implications of transcriptional subtypes determined by the expression of KRT81, HNF1A and GATA6 were examined using immunohistochemistry in advanced (n=139) and resected (n=411) PDAC samples as well as in 57 matched primary tumors and corresponding metastases. RNAseq data of 316 resected PDAC patients was analyzed for validation.

RESULTS

Both subtyping systems were highly interrelated. Subtypes switched during disease progression in up to 31.6% of patients. Transcriptional subtyping had a modest prognostic impact in both unstratified cohorts, but strongly improved outcomes in patients with KRT81 positive / GATA6 negative tumors treated with palliative or adjuvant gemcitabine-based chemotherapy. RNAseq expression data confirmed the findings.

CONCLUSIONS

Transcriptional subtypes have differential responses on palliative and adjuvant gemcitabine- based chemotherapy, but they may change during disease progression. Both employed subtyping systems are equivalent and can be used to inform clinical therapy decisions.

CLINICAL TRIAL REGISTRY

The clinical trial registry identifier isNCT00440167.
Derivation and Internal Validation of Prediction Models for Pulmonary Hypertension Risk Assessment in a Cohort Inhabiting Tibet, China
Authors: Tang Junhui , Yang Rui , Li Hui , Wei Xiaodong , Yang Zhen , Cai Wenbin , Jiang Yao , Zhuo Ga , Meng Li , Xu Yali
Published: April 2024

Background

Due to exposure to hypoxic environments, individuals residing in plateau regions are susceptible to pulmonary hypertension (PH). Consequently, there is an urgent need for a simple and efficient nomogram to assess the risk of PH in this population.

Methods

This study included a total of 6,603 subjects, who were randomly divided into a validation set and a derivation set at a ratio of 7:3. Optimal predictive features were identified through the least absolute shrinkage and selection operator regression technique, and nomograms were constructed using multivariate logistic regression. The performance of these nomograms was evaluated and validated using the area under the curve (AUC), calibration curves, the Hosmer-Lemeshow test, and decision curve analysis. Comparisons between nomograms were conducted using the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indices.

Results

NomogramIwas established based on independent risk factors, including gender, Tibetan ethnicity, age, incomplete right bundle branch block (IRBBB), atrial fibrillation (AF), sinus tachycardia (ST), and T wave changes (TC). The AUCs for NomogramIwere 0.716 in the derivation set and 0.718 in the validation set. NomogramIIwas established based on independent risk factors, including Tibetan ethnicity, age, right axis deviation (RAD), high voltage in the right ventricle (HVRV), IRBBB, AF, pulmonary P waves, ST, and TC. The AUCs for NomogramIIwere 0.844 in the derivation set and 0.801 in the validation set. Both nomograms demonstrated satisfactory clinical consistency. The IDI and NRI indices confirmed that NomogramIIoutperformed NomogramI. Therefore, the online dynamic NomogramIIwas established.

Conclusions

A reliable and straightforward nomogram was developed to predict the risks of PH in the plateau population.
Incidence rate, risk factors and patient reported outcome in patients with a dislocation following hip hemiarthroplasty after acute femoral neck fracture; a scoping review
Authors: Närhi Susanne C. Faurholt , Rasmussen Louise I. E. Ø. , Overgaard Søren , Viberg Bjarke L. , Hermansen Lars L.
Published: April 2024

Objective

The objective of this scoping review of the literature is to find the incidence rate and risk factors for dislocation of hip hemiarthroplasties (HAs) after acute femoral neck fractures (FNFs). Additionally we aim to determine the subjectively reported experience and/or Patient Reported Outcomes (PROs) minimum six months after a dislocation of a hip HA after acute FNF.

Introduction

The existing literature suggests a dislocation rate of 1 – 12%(1-8), and we aim to evaluate the dislocation rates reported in the literature, and explain the differences in the reportings. Some of the suggested risk factors ranging from surgical approach(1, 5, 6), cognitive impairment(2, 5-8), prosthesis type(4) and uncemented vs cemented implant(3). There are no studies summarizing all risk factors for dislocating the hip HA. The patient’s subjective experience after dislocation of a hip HA after acute FNF is not well known. The literature lacks direct information of the patients’ subjective experience after dislocation of the hip HA after acute FNF.

Inclusion criteria

Published articles on the incidence of patients with HA, who develop dislocation. Risk factors for dislocation and patient reported outcomes after reposition of dislocation. Register studies, clinical prospective studies and case-control studies will be included. The lower limit for inclusion of a risk factor will be minimum 5 studies that have minimum 10 patients with dislocation(s).

Methods

This scoping review will be conducted in accordance with the JBI methodology for scoping reviews(9). We will develop a full search strategy for Embase, MEDLINE, PubMed and Cochrane Library. Studies published in English, Swedish, Danish and Norwegian will be included. Studies with other languages will be considered if an appropriate translator is available. The three research questions will be analyzed separately and reported narratively. Despite this being a scoping review, we shall include some risk of bias elements in the analysis.
Location of phosphorylation sites within long polypeptide chains by binder-assisted nanopore detection
Authors: Lan Wei-Hsuan , He Hanxiao , Bayley Hagan , Qing Yujia
Published: April 2024

The detection and mapping of protein phosphorylation sites are essential for understanding the mechanisms of various cellular processes and for identifying targets for drug development. The study of biopolymers at the single-molecule level has been revolutionized by nanopore technology. In this study, we detect protein phosphorylation within long polypeptides (>600 amino acids), after the attachment of binders that interact with phosphate monoesters; electro-osmosis is used to drive the tagged chains through engineered protein nanopores. By monitoring the ionic current carried by a nanopore, phosphorylation sites are located within individual polypeptide chains, providing a valuable step toward nanopore proteomics.
A pervasive large conjugative plasmid mediates multispecies biofilm formation in the intestinal microbiota increasing resilience to perturbations
Authors: García-Bayona Leonor , Said Nathania , Coyne Michael J. , Flores Katia , Elmekki Nazik M. , Sheahan Madeline L. , Camacho Adriana Gutierrez , Hutt Kathryn , Yildiz Fitnat H. , Kovács Ákos T. , Waldor Matthew K. , Comstock Laurie E.
Published: April 2024

Although horizontal gene transfer is pervasive in the intestinal microbiota, we understand only superficially the roles of most exchanged genes and how the mobile repertoire affects community dynamics. Similarly, little is known about the mechanisms underlying the ability of a community to recover after a perturbation. Here, we identified and functionally characterized a large conjugative plasmid that is one of the most frequently transferred elements among Bacteroidales species and is ubiquitous in diverse human populations. This plasmid encodes both an extracellular polysaccharide and fimbriae, which promote the formation of multispecies biofilms in the mammalian gut. We use a hybridization-based approach to visualize biofilms in clarified whole colon tissue with unprecedented 3D spatial resolution. These biofilms increase bacterial survival to common stressors encountered in the gut, increasing strain resiliency, and providing a rationale for the plasmid’s recent spread and high worldwide prevalence.