bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting near-term glaucoma progression: An artificial intelligence approach using clinical free-text notes and data from electronic health records
Authors: Jalamangala Shivananjaiah Sunil K. , Kumari Sneha , Majid Iyad , Wang Sophia Y.
Published: April 2023

Purpose

The purpose of this study was to develop a model to predict whether or not glaucoma will progress to the point of requiring surgery within the following year, using data from electronic health records (EHRs), including both structured data and free-text progress notes.

Methods

A cohort of adult glaucoma patients was identified from the EHR at Stanford University between 2008 and 2020, with data including free-text clinical notes, demographics, diagnosis codes, prior surgeries, and clinical information, including intraocular pressure, visual acuity, and central corneal thickness. Words from patients’ notes were mapped to ophthalmology domain-specific neural word embeddings. Word embeddings and structured clinical data were combined as inputs to deep learning models to predict whether a patient would undergo glaucoma surgery in the following 12 months using the previous 4-12 months of clinical data. We also evaluated models using only structured data inputs (regression-, tree-, and deep-learning-based models) and models using only text inputs.

Results

Of the 3,469 glaucoma patients included in our cohort, 26% underwent surgery. The baseline penalized logistic regression model achieved an area under the receiver operating curve (AUC) of 0.873 and F1 score of 0.750, compared with the best tree-based model (random forest, AUC 0.876; F1 0.746), the deep learning structured features model (AUC 0.885; F1 0.757), the deep learning clinical free-text features model (AUC 0.767; F1 0.536), and the deep learning model with both the structured clinical features and free-text features (AUC 0.899; F1 0.745).

Discussion

Fusion models combining text and EHR structured data successfully and accurately predicted glaucoma progression to surgery. Future research incorporating imaging data could further optimize this predictive approach and be translated into clinical decision support tools.
Outer Membrane Vesicles From Fusobacterium nucleatum Switch M0-Like Macrophages Toward the M1 Phenotype to Destroy Periodontal Tissues in Mice
Authors: Chen Gang , Sun Qiang , Cai QiaoLing , Zhou HongWei
Published: April 2023

Periodontitis is a chronic inflammatory oral disease that affects nearly 50% of all adults. Fusobacterium nucleatum (F. nucleatum) is known to be involved in the formation and development of periodontitis. Outer membrane vesicles (OMVs) harboring toxic bacterial components are continuously released during F. nucleatum growth and regulate the extent of the inflammatory response by controlling the functions of immune and non-immune cells in tissues. Macrophages are important immune cells in periodontal tissue that resist pathogen invasion and play an important role in the pathophysiological process of periodontitis. However, the role of the interaction between F. nucleatum OMVs and macrophages in the occurrence and development of periodontitis has not been studied. The purpose of this study was to clarify the effect of F. nucleatum OMVs on the polarization of macrophages and the roles of this specific polarization and F. nucleatum OMVs in the pathophysiology of periodontitis. The periodontitis model was established by inducing ligation in C57BL/6 mice as previously described. Micro-CT, RT-qPCR, hematoxylin-eosin (H&E) and tartrate acid phosphatase (TRAP) staining assays were performed to analyze the periodontal tissue, alveolar bone loss, number of osteoclasts and expression of inflammatory factors in gingival tissue. The changes in the state and cytokine secretion of bone marrow-derived macrophages (BMDMs) stimulated by F. nucleatum OMVs were observed in vivo by confocal microscopy, flow cytometry, Western blot and ELISA. Mouse gingival fibroblasts (MGFs) were isolated and then cocultured with macrophages. The effects of F. nucleatum OMVs on the proliferation and apoptosis of MGFs were analyzed by flow cytometry and lactate dehydrogenase (LDH) assays. The periodontitis symptoms of mice in the F. nucleatum OMVs + ligation group were more serious than those of mice in the simple ligation group, with more osteoclasts and more inflammatory factors (IL-1β, IL-6, and TNF-α) being observed in their gingival tissues. M0 macrophages transformed into M1 macrophages after the stimulation of BMDMs with F. nucleatum OMVs, and the M1 macrophages then released more inflammatory cytokines. Analysis of the coculture model showed that the MGF apoptosis and LDH release in the inflammatory environment were increased by F. nucleatum OMV treatment. In conclusion, F. nucleatum OMVs were shown to aggravate periodontitis, alveolar bone loss and the number of osteoclasts in an animal model of periodontitis. F. nucleatum OMVs promoted the polarization of macrophages toward the proinflammatory M1 phenotype, and the inflammatory environment further aggravated the toxicity of F. nucleatum OMVs on MGFs. These results suggest that M1 macrophages and F. nucleatum OMVs play roles in the occurrence and development of periodontitis.
The Herb Pair Radix Rehmanniae and Cornus Officinalis Attenuated Testicular Damage in Mice With Diabetes Mellitus Through Butyric Acid/Glucagon-Like Peptide-1/Glucagon-Like Peptide-1 Receptor Pathway Mediated by Gut Microbiota
Authors: Chen Yuping , Song Siyuan , Shu Anmei , Liu Liping , Jiang Jinjin , Jiang Ming , Wu Qin , Xu Huiqin , Sun Jihu
Published: April 2023

Graphical Abstract

A diagram illustrating the alleviating effect of the herb pair RR-CO on testicular damage in diabetes mellitus by modulating the butyrate/GLP-1/GLP-1R pathway mediated by gut microbiota.
Elder and booster vaccination associates with decreased risk of serious clinical outcomes in comparison of Omicron and Delta variant: A meta-analysis of SARS-CoV-2 infection
Authors: Wu Yanhua , Pan Yuchen , Su Kaisheng , Zhang Yangyu , Jia Zhifang , Yi Jiaxin , Lv Haiyong , Zhang Lihuan , Xue Mingyang , Cao Donghui , Jiang Jing
Published: April 2023

Background

The COVID-19 pandemic brings great pressure to the public health systems. This meta-analysis aimed to compare the clinical outcomes among different virus variants, to clarify their impact on medical resources and to provide evidence for the formulation of epidemic prevention policies.

Methods

A systematic literature search was performed in the PubMed, Embase, and Cochrane Library databases using the key words “Omicron” and “Delta.” The adjusted Risk ratios (RRs), Odds ratios (ORs) and Hazard ratios (HRs) were extracted, and RRs and Rate difference % (RD%) were used to interpret the risk estimates of the outcomes ultimately.

Results

Forty-three studies were included, with 3,812,681 and 14,926,841 individuals infected with SARS-CoV-2 Delta and Omicron variant, respectively. The relative risks of hospitalization, death, ICU admission, and mechanical ventilation use after infection with the Omicron variant were all significantly reduced compared those after infection with the Delta variant (RRhospitalization = 0.45, 95%CI: 0.40–0.52; RRdeath = 0.37, 95%CI: 0.30–0.45; RRICU = 0.35, 95%CI: 0.29–0.42; RRmechanical ventilation = 0.33, 95%CI: 0.25–0.44). The change of both absolute and relative risks for hospitalization was more evident (RR = 0.47, 95%CI: 0.42–0.53；RD% =10.61, 95%CI: 8.64–12.59) and a significant increase was observed for the absolute differences in death in the elderly (RD% = 5.60, 95CI%: 4.65–6.55); the change of the absolute differences in the risk of hospitalization and death were most markedly observed in the patients with booster vaccination (RD%hospitalization = 8.60, 95CI%: 5.95–11.24; RD%death = 3.70, 95CI%: 0.34–7.06).

Conclusion

The ability of the Omicron variant to cause severe clinical events has decreased significantly, as compared with the Delta variant, but vulnerable populations still need to be vigilant. There was no interaction between the vaccination doses and different variants.
Fecal microbiome transplant from patients with lactation mastitis promotes mastitis in conventional lactating mice
Authors: Kong Chao-Yue , Yang Yi-Qin , Han Bing , Chen Hui-Ling , Mao Yu-Qin , Huang Jia-Ting , Wang Li-Shun , Li Zhan-Ming
Published: April 2023

Introduction

Lactation mastitis seriously severely affects the health of lactating females and their infants, yet the underlying causes of clinical lactation mastitis remain unclear.

Methods

In this study, we used microbiota-humanized mice as a model to investigate the role of gut microbiota in lactation mastitis. We compared the fecal microbiota of lactation mastitis patients and healthy individuals and conducted fecal microbiota transplantation (FMT) experiments in an antibiotic-pretreated mouse model to test whether gut microbes contribute to human lactation mastitis.

Results

Our results showed that gut microbiota diversity was reduced and dysbiosis was present in lactating mastitis patients. FMT from lactation mastitis patients (M-FMT), but not from healthy individuals (H-FMT), to antibiotic-treated mice resulted in lactation mastitis. The inflammation in mice caused by gut microbiota from lactating mastitis patients appears to be pervasive, as hepatocytes from mice that received feces from lactating mastitis patients showed marked swelling. In addition, serum pro-inflammatory factors, including IL-4, IL-17, MPO, IL-6, IL-1β, and TNF-α, were significantly increased in the M-FMT group. The Firmicutes/Bacteroidetes ratio (F/B), a biomarker of gut dysbiosis, was significantly increased in the M-FMT group. At the phylum level, Actinobacteria were significantly increased, and Verrucomicrobia were significantly decreased in the M-FMT group. At the genus level, Ruminococcus and Faecalibacterium were significantly reduced, while Parabacteroides were significantly increased in the feces of both patients with lactation mastitis and M-FMT mice. Moreover, our study revealed an “amplification effect” on microbiota differences and mastitis disease following human-to-mouse FMT.

Conclusion

Collectively, our findings demonstrate that the gut microbiota in lactating mastitis patients is dysbiotic and contributes to the pathogenesis of mastitis.
The natural product, echinatin, protects mice from methicillin-resistant Staphylococcus aureus pneumonia by inhibition of alpha-hemolysin expression
Authors: Zhang Wei , Gong Qing , Tang Zhitong , Ma Xin , Wang Zhuoer , Guan Jiyu , Wang Li , Zhao Yicheng , Yan Ming
Published: April 2023

Antimicrobial resistance (AMR) is a global, multifaceted crisis that poses significant challenges to the successful eradication of devastating pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA), a persistent superbug that causes devastating infections. The scarcity of new antibacterial drugs is obvious, and antivirulence strategies that reduce the pathogenicity of bacteria by weakening their virulence have become the subject of intense investigation. Alpha-hemolysin (Hla), a cytolytic pore-forming toxin, has a pivotal role in S. aureus pathogenesis. Here, we demonstrated that echinatin, a natural compound isolated from licorice, effectively inhibited the hemolytic activity of MRSA at 32 μg/mL. In addition, echinatin did not interfere with bacterial growth and had no significant cytotoxicity at the inhibitory concentration of S. aureus hemolysis. Heptamer formation tightly correlated with Hla-mediated cell invasion, whereas echinatin did not affect deoxycholic acid-induced oligomerization of Hla. Echinatin affected hemolytic activity through indirect binding to Hla as confirmed by the neutralization assay and cellular thermal shift assay (CETSA). Furthermore, qRT–PCR and western blot analyses revealed that echinatin suppressed Hla expression at both the mRNA and protein levels as well as the transcript levels of Agr quorum-sensing system-related genes. Additionally, when echinatin was added to a coculture system of A549 cells and S. aureus, it significantly reduced cell damage. Importantly, echinatin exhibited a significant therapeutic effect in an MRSA-induced mouse pneumonia model. In conclusion, the present findings demonstrated that echinatin significantly inhibits the hemolysin effect and may be a potential candidate compound for combating drug-resistant MRSA infections.
Bridging preclinical and clinical gut microbiota research using the ex vivo SIFR® technology
Authors: Van den Abbeele Pieter , Deyaert Stef , Thabuis Clémentine , Perreau Caroline , Bajic Danica , Wintergerst Eva , Joossens Marie , Firrman Jenni , Walsh Dana , Baudot Aurélien
Published: April 2023

Introduction

While modulation of the human adult gut microbiota is a trending strategy to improve health, the underlying mechanisms are poorly understood.

Methods

This study aimed to assess the predictive value of the ex vivo, reactor-based, high-throughput SIFR® (Systemic Intestinal Fermentation Research) technology for clinical findings using three structurally different prebiotics [inulin (IN), resistant dextrin (RD) and 2′-fucosyllactose (2′FL)].

Results

The key finding was that data obtained within 1–2 days were predictive for clinical findings upon repeated prebiotic intake over weeks: among hundreds of microbes, IN stimulated Bifidobacteriaceae, RD boosted Parabacteroides distasonis, while 2′FL specifically increased Bifidobacterium adolescentis and Anaerobutyricum hallii. In line with metabolic capabilities of these taxa, specific SCFA (short-chain fatty acids) were produced thus providing insights that cannot be obtained in vivo where such metabolites are rapidly absorbed. Further, in contrast to using single or pooled fecal microbiota (approaches used to circumvent low throughput of conventional models), working with 6 individual fecal microbiota enabled correlations that support mechanistic insights. Moreover, quantitative sequencing removed the noise caused by markedly increased cell densities upon prebiotic treatment, thus allowing to even rectify conclusions of previous clinical trials related to the tentative selectivity by which prebiotics modulate the gut microbiota. Counterintuitively, not the high but rather the low selectivity of IN caused only a limited number of taxa to be significantly affected. Finally, while a mucosal microbiota (enriched with Lachnospiraceae) can be integrated, other technical aspects of the SIFR® technology are a high technical reproducibility, and most importantly, a sustained similarity between the ex vivo and original in vivo microbiota.

Discussion

By accurately predicting in vivo results within days, the SIFR® technology can help bridge the so-called “Valley of Death” between preclinical and clinical research. Facilitating development of test products with better understanding of their mode of action could dramatically increase success rate of microbiome modulating clinical trials.

Graphical Abstract
Fungal succession in decomposing ash leaves colonized by the ash dieback pathogen Hymenoscyphus fraxineus or its harmless relative Hymenoscyphus albidus
Authors: Kosawang Chatchai , Børja Isabella , Herrero Maria-Luz , Nagy Nina E. , Nielsen Lene R. , Solheim Halvor , Timmermann Volkmar , Hietala Ari M.
Published: April 2023

Introduction

The ascomycete Hymenoscyphus fraxineus, originating from Asia, is currently threatening common ash (Fraxinus excelsior) in Europe, massive ascospore production from the saprotrophic phase being a key determinant of its invasiveness.

Methods

To consider whether fungal diversity and succession in decomposing leaf litter are affected by this invader, we used ITS-1 metabarcoding to profile changes in fungal community composition during overwintering. The subjected ash leaf petioles, collected from a diseased forest and a healthy ash stand hosting the harmless ash endophyte Hymenoscyphus albidus, were incubated in the forest floor of the diseased stand between October 2017 and June 2018 and harvested at 2–3-month intervals.

Results

Total fungal DNA level showed a 3-fold increase during overwintering as estimated by FungiQuant qPCR. Petioles from the healthy site showed pronounced changes during overwintering; ascomycetes of the class Dothideomycetes were predominant after leaf shed, but the basidiomycete genus Mycena (class Agaricomycetes) became predominant by April, whereas H. albidus showed low prevalence. Petioles from the diseased site showed little change during overwintering; H. fraxineus was predominant, while Mycena spp. showed increased read proportion by June.

Discussion

The low species richness and evenness in petioles from the diseased site in comparison to petioles from the healthy site were obviously related to tremendous infection pressure of H. fraxineus in diseased forests. Changes in leaf litter quality, owing to accumulation of host defense phenolics in the pathogen challenged leaves, and strong saprophytic competence of H. fraxineus are other factors that probably influence fungal succession. For additional comparison, we examined fungal community structure in petioles collected in the healthy stand in August 2013 and showing H. albidus ascomata. This species was similarly predominant in these petioles as H. fraxineus was in petioles from the diseased site, suggesting that both fungi have similar suppressive effects on fungal richness in petiole/rachis segments they have secured for completion of their life cycle. However, the ability of H. fraxineus to secure the entire leaf nerve system in diseased forests, in opposite to H. albidus, impacts the general diversity and successional trajectory of fungi in decomposing ash petioles.
Sweetening K-channels: what sugar taught us about permeation and gating
Authors: Naranjo David , Diaz-Franulic Ignacio
Published: April 2023

Because they enable for the modification of both viscosity and osmolarity, sugars have been used as a biophysical probe of voltage-gated K-channels for a while. Viscosity variations made it possible to measure the pore sizes in large and small conductance K-channels using techniques similar to those used in the 1980s to study the gramicidin A channel. These analyses led to the finding that the size of the internal mouth appears to be the primary cause of the conductance differences between Shaker-like channels and large conductance BK-channels. As an osmotic agent, adding sugar unilaterally causes streaming potentials that indicate H2O/K+ cotransport across the BK-channel pore. Osmotic experiments on Shaker K-channels suggest that the pore gate operation and the slow inactivation displace comparable amounts of water. Functionally isolated voltage sensors allow estimation of individual osmotic work for each voltage sensing charge during voltage-activation, reporting dramatic internal and external remodeling of the Voltage Sensing Domain´s solvent exposed surfaces. Remarkably, each charge of the VSD appears to take a unique trajectory. Thus, manipulation of viscosity and osmolarity, together with 3D structures, brings in solid grounds to harmonize function and structure in membrane proteins such as K-channels and, in a wider scope, other structurally dynamic proteins.
Outcome after endovascular treatment for acute ischemic stroke by underlying etiology: Tertiary experience and meta-analysis
Authors: Ma Chunlin , Cao Wenbo , Huang Yang , Tian Qiuyue , Chen Yanfei , Wang Yabing , Chen Jian , Gao Peng , Dmytriw Adam A. , Regenhardt Robert W. , Chen Fei , Ma Qingfeng , Jiao Liqun , Yang Bin
Published: April 2023

Objective

To investigate the effect of two major etiologies [intracranial atherosclerotic stenosis (ICAS) and cardioembolism (CE])] on outcomes of acute ischemic stroke (AIS) patients due to large vessel occlusion (LVO) after endovascular thrombectomy (EVT).

Methods

Anterior circulation AIS patients receiving EVT were retrospectively analyzed. Clinical and laboratory data were collected. Clinical outcomes including favorable outcome (90-day modified Rankin Scale 0–2), mortality, intracranial hemorrhage (ICH) and symptomatic ICH (sICH) were compared. A systematic review and meta-analysis was also performed.

Results

A total of 302 AIS patients were included and divided into the ICAS group (86 patients) and the CE group (216 patients). Patients in the ICAS group were younger (62[18.0] vs. 68[19.0] years, p < 0.001), more likely to have smoking (52.3% vs. 26.9%, p < 0.001) and drinking (52.3% vs. 23.1%, p < 0.001) history, and more frequently required rescue therapy (80.2% vs. 4.6%, p < 0.001) compared to the CE group. However, favorable outcome (aOR 0.722, 95%CI 0.372–1.402, p = 0.336) and mortality (aOR 1.522, 95%CI 0.606–3.831, p = 0.371) were not significantly different between the two groups before and after adjustment. The incidence of sICH and ICH were comparable between the two groups before and after adjustment. Systematic review and meta-analysis consisted of 8 eligible studies (7 previous studies and this current study), incorporating 552 ICAS patients and 1,402 CE patients. Favorable outcome was slightly more likely in the ICAS group compared to the CE group (54.2% vs. 46.3%, OR 1.40, 95%CI 1.00–1.96, I2 = 53.2%). Moreover, the ICAS group had a lower rate of mortality (14.3% vs. 22.2%, OR 0.63, 95%CI 0.46–0.87, I2 = 0.0%) and ICH (19.5% vs. 31.9%, OR 0.60, 95%CI 0.42–0.84, I2 = 0.0%) than the CE group, while the two groups were similar in sICH rate (5.9% vs. 6.7%, OR 0.94, 95%CI 0.55–1.60, I2 = 6.3%).

Conclusion

Etiology was not considered as an important factor in functional outcome, despite the differences in baseline characteristics and technical EVT approach. The current study of anterior circulation AIS-LVO patients supports that outcomes for those with ICAS are not significantly different from those with CE.
Endovascular recanalization of symptomatic non-acute occlusion of the vertebrobasilar artery
Authors: Zhou ZhiLong , Li TianXiao , Zhu LiangFu , Wu LiHeng , Guan Min , Ma ZhenKai , Liu YangHui , Qin Jin , Gao BuLang
Published: April 2023

Purpose

The study aimed to investigate the safety, effect, and risk factors of endovascular recanalization of symptomatic non-acute occlusion of the vertebrobasilar artery (SNOVA).

Materials and methods

Patients with SNOVA were retrospectively enrolled and treated with endovascular recanalization. The clinical data, endovascular treatment, peri-procedural complications, and follow-up outcomes were analyzed.

Results

A total of 88 patients were enrolled, with an interval to recanalization of 2–89 days (median 23) and an mRS of 2–5 (median 3 and IQR 1). Occlusion was in the intracranial vertebral artery in 68 (77.27%) patients and basilar artery in 20 (22.73%), with an occlusion length of 4.5–43.7 mm (mean 18.3 ± 8.8). Endovascular recanalization was successful in 81 (92.0%) patients. Post-dilatation was performed in 23 (28.4%) patients. After stenting, the residual stenosis was 10%–40% (mean 20.2% ± 7.6%). Peri-procedural complications occurred in 17 (19.3%) patients, with a mortality rate of 5.7%. In total, 79 (95.18%) patients underwent follow-up 5–29 (mean 16.9 ± 5.5) months later, with an mRS score of 0–6 (median 1 and IQR 1) at follow-up, being significantly (p < 0.0001) better than that at discharge. Stroke occurred in 9 patients (11.4%) in 1 year. In-stent restenosis occurred in 19 (25.33%) patients. Significant (p < 0.05) independent risk factors were blunt occlusion for successful recanalization, duration to recanalization and blunt occlusion for peri-procedural complications, and post-dilatation for both in-stent restenosis and 1-year stroke or death events.

Conclusion

Endovascular recanalization of symptomatic non-acute occlusion of the vertebrobasilar artery is feasible even for a long occlusion segment, with a high recanalization rate, a low complication rate, and a good prognosis. Blunt occlusion and duration from the onset to recanalization may affect successful recanalization and peri-procedural complications while post-dilatation may affect in-stent restenosis and prognosis.
Unmet needs of people with epilepsy: A qualitative study exploring their journey from presentation to long-term management across five European countries
Authors: Graham-Rowe Ella , Katzer Caroline Brigitte , Riaz Sumira , Attwood Amanda , Bates Liz , Sainz-Fuertes Ricardo , Swan Becky
Published: April 2023

Introduction

Epilepsy is a neurological disease that can negatively impact a person’s physical, psychological, social, and emotional well-being. The aim of this study was to provide insights into the experiences of people with epilepsy on polytherapy (i.e., people on a combination of two or more anti-seizure medications [ASMs]), with an emphasis on their emotional journey.

Methods

Market research was conducted with 40 people with epilepsy from France, Germany, Italy, Spain, and the United Kingdom. Semi-structured interviews were analyzed using both a content and framework analysis approach. A content analysis of participants’ expressed emotions was used to illustrate the changes of emotions experienced by people with epilepsy from presentation through to monitoring and follow-up stages.

Results

In each stage of the journey, themes and subthemes were identified under the overarching headings: Stage 1: Presentation – Life is turned upside down; Stage 2: Diagnosis – Period of learning; Stage 3: Treatment – Aspirations and experimentation; and Stage 4: Monitoring and follow-up – Feeling “out on a limb”. The research identified key unmet needs and opportunities for people with epilepsy to improve their subjective experiences at different stages of their disease journey, namely: (1) establish and promote support networks from presentation through to monitoring and follow-up stages; (2) accelerate pathway to diagnosis; (3) provide opportunities to discuss the diagnosis with patients; (4) clarify treatment-change guidelines for patients; and (5) develop a shared treatment decision-making/empowerment tool.

Discussion

The research findings and recommendations have the potential to drive change at an individual level, as well as at a healthcare level.
Preoperative percutaneous Onyx embolization of carotid body paragangliomas with balloon test occlusion
Authors: Kelblová Martina , Vaníček Jiří , Gál Břetislav , Rottenberg Jan , Bulik Martin , Cimflová Petra , Křivka Tomáš
Published: April 2023

Objectives

The study aims to analyze our first experience with direct percutaneous embolization of carotid body tumors (CBTs) using ethylene-vinyl alcohol copolymer (Onyx) along with balloon test occlusion (BTO).

Methods

A retrospective preliminary single-center study was conducted at the Otorhinolaryngology and Head and Neck Surgery Department and the Medical Imaging Department of the University Teaching Hospital. A consecutive series of three patients with CBTs was treated at the local institution between October 2018 and June 2019. All three patients underwent preoperative percutaneous embolization using ethylene-vinyl alcohol copolymer (Onyx 18) with the addition of BTO. Outcome measures were the percentage of tumor devascularization, intraoperative blood losses, and operation times. BTO was evaluated by clinical neurological examination and neurosonological transcranial Doppler examination of the middle cerebral artery (MCA).

Results

Devascularization of all three tumors was complete or near complete. All three tumors were surgically extirpated with excellent surgical outcomes. The blood losses were minimal, and the average operation time was 2 h and 8 min. BTO was positive in one patient, which was valuable additional information on carotid branches ligation limitations. The other two patients showed negative BTOs with the result of safety of eventual carotid arteries ligations.

Conclusion

Preoperative direct percutaneous embolization of CBT with Onyx is a highly effective procedure that significantly facilitates surgery. BTO provides valuable additional information on the most appropriate and safe surgical approach.
Ketogenic diet for super-refractory status epilepticus (SRSE) with NORSE and FIRES: Single tertiary center experience and literature data
Authors: Nabbout Rima , Matricardi Sara , De Liso Paola , Dulac Olivier , Oualha Mehdi
Published: April 2023

Background and purpose

Ketogenic diet (KD) is an emerging treatment option for super-refractory status epilepticus (SRSE). We evaluated the effectiveness of KD in patients presenting SRSE including NORSE (and its subcategory FIRES).

Methods

A retrospective review of the medical records was performed at the Necker Enfants Malades Hospital. All children with SRSE in whom KD was started during the last 10 years were included. A systematic search was carried out for all study designs, including at least one patient of any age with SRSE in whom KD was started. The primary outcome was the responder rate and Kaplan–Meier survival curves were generated for the time-to-KD response. As secondary outcomes, Cox proportional hazard models were created to assess the impact of NORSE-related factors on KD efficacy.

Results

Sixteen children received KD for treatment of SRSE, and three had NORSE presentation (one infectious etiology, two FIRES). In medical literature, 1,613 records were initially identified, and 75 were selected for review. We selected 276 patients receiving KD during SRSE. The most common etiology of SRSE was acute symptomatic (21.3%), among these patients, 67.7% presented with NORSE of immune and infectious etiologies. Other etiologies were remote symptomatic (6.8%), progressive symptomatic (6.1%), and SE in defined electroclinical syndromes (14.8%), including two patients with genetic etiology and NORSE presentation. The etiology was unknown in 50.7% of the patients presenting with cryptogenic NORSE, of which 102 presented with FIRES. Overall, most patients with NORSE benefit from KD (p < 0.004), but they needed a longer time to achieve RSE resolution after starting KD compared with other non-NORSE SRSE (p = 0.001). The response to KD in the NORSE group with identified etiology compared to the cryptogenic NORSE was significantly higher (p = 0.01), and the time to achieve SE resolution after starting KD was shorter (p = 0.04).

Conclusions

The search for underlying etiology should help to a better-targeted therapy. KD can have good efficacy in NORSE; however, the time to achieve SE resolution seems to be longer in cryptogenic cases. These findings highlight the therapeutic role of KD in NORSE, even though this favorable response needs to be better confirmed in prospective controlled studies.
Saccular functions differ for Meniere’s disease with and without coexisting headaches
Authors: Inui Takaki , Kuriyama Tatsuro , Moriyama Kou , Shirai Takeo , Sudo Tomoyuki , Ayani Yusuke , Ozaki Akiko , Inaka Yuko , Araki Michitoshi , Haginomori Shin-Ichi , Kawata Ryo
Published: April 2023

Objectives

To elucidate the differences between the cases of Meniere’s disease (MD) with and without coexisting headaches, especially migraine. The clinical characteristics and vestibular functions are compared.

Subjects

Fifteen patients with definite unilateral MD without headaches (MD/H−; 10 males and 5 females; mean age of 55.8 years), and 20 patients with definite unilateral MD with headaches (MD/H+; 3 males and 17 females; mean age of 54.4 years; 15 cases of migraine without aura and 5 cases of suspected migraine or tension-type headache) were enrolled.

Methods

The medical records, caloric test results, and cervical vestibular evoked myogenic potential (cVEMP) of the patients were reviewed. A monothermal caloric test by injection of cold water was performed, and canal paresis was assessed. cVEMP was recorded using 500 Hz short tone bursts, and the asymmetry ratio using the corrected amplitude of p13–n23 was determined.

Results

The patients in the MD/H− group were predominantly male, whereas more female patients were seen in MD/H+ group (p = 0.004). In the MD/H+ group, the frequency of vertigo and the dizziness handicap inventory (DHI) values were significantly higher than those in the MD/H− group (p = 0.045, <0.001, respectively). There was no statistical difference in the ages, duration of illness, or the hearing levels between both groups. The caloric testing results were abnormal for 10 of the 13 MD/H− cases, and 14 of the 16 MD/H+ cases, which revealed no significant difference between both groups. The cVEMP results revealed positive saccular dysfunction based on the asymmetry ratio of 4 of the 15 MD/H− cases, and 14 of the 20 MD/H+ cases; it was significantly more prevalent in the MD/H+ group than in the MD/H− group (p = 0.018). Multivariate analysis of sex, frequency of vertigo, DHI, and cVEMP results showed significant differences only in the cVEMP results (p = 0.049).

Conclusion

The present study revealed differences in patients with MD depending on the presence or absence of headaches. MD without headaches showed a significant male preponderance. MD with coexisting headaches was more associated with severe saccular dysfunctions than MD without headaches. Concomitant headache may affect the manifestations of the vestibular function, especially in the sacculus, in MD cases.
Functional investigation and two-sample Mendelian randomization study of neuropathic pain hub genes obtained by WGCNA analysis
Authors: Zeng Jianfeng , Lai Cong , Luo Jianwei , Li Li
Published: April 2023

Objective

Neuropathic pain as a complex chronic disease that occurs after neurological injury, however the underlying mechanisms are not clarified in detail, hence therapeutic options are limited. The purpose of this study was to explore potential hub genes for neuropathic pain and evaluate the clinical application of these genes in predicting neuropathic pain.

Methods

Differentially expressed analysis and weighted gene co-expression network analysis (WGCNA) was used to explore new neuropathic pain susceptibility modules and hub genes. KEGG and GO analyses was utilized to explore the potential role of these hub genes. Nomogram model and ROC curves was established to evaluate the diagnostic efficacy of hub genes. Additionally, the correlation of IL-2 with immune infiltration was explored. Finally, a Mendelian randomization study was conducted to determine the causal effect of IL-2 on neuropathic pain based on genome-wide association studies.

Results

WGCNA was performed to establish the networks of gene co-expression, screen for the most relevant module, and screen for 440 overlapping WGCNA-derived key genes. GO and KEGG pathway enrichment analyses demonstrated that the key genes were correlated with cytokine receptor binding, chemokine receptor binding, positive regulation of JAK–STAT cascade, chemokine-mediated signaling pathway, PI3K-AKT pathway and chemokine pathway. Through Cytoscape software, top ten up-regulated genes with high scores were IL2, SMELL, CCL4, CCR3, CXCL1, CCR1, HGF, CXCL2, GATA3, and CRP. In addition, nomogram model performed well in predicting neuropathic pain risk, and with the ROC curve, the model was showed to be effective in diagnosis. Finally, IL2 was selected and we observed that IL2 was causally associated with immune cell infiltrates in trigeminal neuralgia. In inverse variance weighting, we found that IL2 was associated with the risk of trigeminal neuralgia with an OR of 1.203 (95% CI = 1.004–1.443, p = 0.045).

Conclusion

We constructed a WGCNA-based co-expression network and identified neuropathic pain-related hub genes, which may offer further insight into pre-symptomatic diagnostic approaches and may be useful for the study of molecular mechanisms for understanding neuropathic pain risk genes.
Lonicera caerulea Berry Polyphenols Extract Alleviates Exercise Fatigue in Mice by Reducing Oxidative Stress, Inflammation, Skeletal Muscle Cell Apoptosis, and by Increasing Cell Proliferation
Authors: Liu Suwen , Meng Fanna , Zhang Dong , Shi Donglin , Zhou Junyi , Guo Shuo , Chang Xuedong
Published: April 2023

Exercise fatigue can exert deleterious effects on the body. This study evaluated the effects and mechanisms by which Lonicera caerulea berry polyphenols extract (LCBP) improved the treadmill endurance of mice. Comparison was performed between the effects at 25°C and low temperatures (-5°C). Energy storage, product metabolism, and other biochemical indices were determined using vitamin C (VC) as a positive control. Co-immunoprecipitation was performed to detect the interaction between different proteins. Dietary supplementation with LCBP significantly prolonged the exhaustion time during treadmill exercise by 20.4% (25 °C) and 27.4% (-5 °C). LCBP significantly regulated the expression of antioxidant and inflammatory proteins, Bcl-2 /Bax apoptosis proteins, and the PKCα -NOx2 / Nox4 pathway proteins, and activated the expression of AMPK-PGC1α -NRF1-TFAM proteins in skeletal muscle mitochondria. The gene and protein expression of miRNA-133a/IGF-1/PI3K/Akt/mTOR in skeletal muscle cells was also activated. Molecular docking confirmed that the main components of LCBP such as cyanidin-3-glucoside, catechin, and chlorogenic acid, have strong binding affinity toward AMPKα. LCBP alleviates exercise fatigue in mice by reducing oxidative stress, inflammation, and apoptosis of skeletal muscle cells, enhances mitochondrial biosynthesis and cell proliferation, reduces fatigue, and enhances performance. These effects are also significant in a low-temperature environment (Graphical Abstract). Consequently, these results provide novel insights into the anti- fatigue roles of LCBP in exercise fatigue.
The RNA cargo in small extracellular vesicles from chicken eggs is bioactive in C57BL/6 J mice and human peripheral blood mononuclear cells ex vivo
Authors: Fratantonio Deborah , Munir Javaria , Shu Jiang , Howard Katherine , Baier Scott R. , Cui Juan , Zempleni Janos
Published: April 2023

Small extracellular vesicles (sEVs) and their RNA cargo in milk are bioavailable in humans, pigs, and mice, and their dietary depletion and supplementation elicits phenotypes. Little is known about the content and biological activity of sEVs in foods of animal origin other than milk. Here we tested the hypothesis that sEVs in chicken eggs (Gallus gallus) facilitate the transfer of RNA cargo from an avian species to humans and mice, and their dietary depletion elicits phenotypes. sEVs were purified from raw egg yolk by ultracentrifugation and authenticated by transmission electron microscopy, nano-tracking device, and immunoblots. The miRNA profile was assessed by RNA-sequencing. Bioavailability of these miRNAs in humans was assessed by egg feeding study in adults, and by culturing human peripheral blood mononuclear cells (PBMCs) with fluorophore-labeled egg sEVs ex vivo. To further assess bioavailability, fluorophore-labeled miRNAs, encapsulated in egg sEVs, were administered to C57BL/6 J mice by oral gavage. Phenotypes of sEV RNA cargo depletion were assessed by feeding egg sEV and RNA-defined diets to mice and using spatial learning and memory in the Barnes and water mazes as experimental readouts. Egg yolk contained 6.30 × 1010 ± 6.06 × 109 sEVs/mL, which harbored eighty-three distinct miRNAs. Human PBMCs internalized sEVs and their RNA cargo. Egg sEVs, loaded with fluorophore-labeled RNA and administered orally to mice, accumulated primarily in brain, intestine and lungs. Spatial learning and memory (SLM) was compromised in mice fed on egg sEV- and RNA-depleted diet compared to controls. Egg consumption elicited an increase of miRNAs in human plasma. We conclude that egg sEVs and their RNA cargo probably are bioavailable. The human study is registered as a clinical trial and accessible at https://www.isrctn.com/ISRCTN77867213.
Late Mortality, Subsequent Malignant Neoplasms and Hospitalisations in Long-Term Survivors of Adolescent and Young Adult Hematological Cancers
Authors: Trama Annalisa , Vener Claudia , Lasalvia Paolo , Bernasconi Alice ,   the Ada Working Group
Published: April 2023

Background

Increased success in the treatment of hematological cancers contributed to the increase of 5-year survival for most adolescent and young adults (AYAs) with these tumours. However, as 5-year survival increased, it became clear that AYA long-term survivors were at increased risk for severe late effects. Moreover, limited information on long-term cancer impact is available for AYAs, since most studies focused on children and adolescents. We aimed to assess various long-term outcomes on AYA survivors of hematological cancers.

Methods

We selected patients diagnosed with a first primary hematological cancer between 1997 and 2006, in the Italian nationwide population-based cohort of AYA cancer survivors (i.e. alive at least 5 years after cancer diagnosis). Long-term outcomes of interest were: second malignant neoplasms (SMNs), hospitalizations and overall mortality. We calculated standardized incidence ratios (SIRs), standardized hospitalization rate ratios (SHRs) and standardized mortality rate ratios (SMRs). To study morbidity patterns over time, we modeled observed incidence rates by fitting flexible parametric models for nonlinear patterns and we used linear regression for linear patterns.

Results

The study cohort included 5,042 AYA hematological cancer survivors of which 1,237 and 3,805 had a leukaemia and lymphoma diagnosis, respectively. AYA survivors were at substantially increased risk for SMN (SIR=2.1; 95%CI=1.7; 2.6), hospitalisation (SHR=1.5; 95%CI=1.5; 1.6), and mortality (SMR=1.4; 95%CI=1.2; 1.6) with differences between leukaemia and lymphoma survivors. The highest excess risks of hospitalisations were for infectious diseases, respiratory diseases, and diseases of blood and blood-forming organs. The morbidity pattern differs over time by morbidity type.

Conclusions

Our results support the need for strict follow-up plans for survivors, and call for further study to better personalised follow-up plans for AYA cancer survivors.
Efficacy and safety of combined immunotherapy and stereotactic radiosurgery in NSCLCBM patients and a novel prognostic nomogram: A real-world study
Authors: Bashir Shoaib , Wen Lei , Zhang Ping , Ye Minting , Li Yin , Hong Weiping , Zhen Junjie , Lai Mingyao , Wang Hui , Yang Yanying , Chen Xingrui , Luo Rishun , Jia Guoxia , Guo Yao , Cai Linbo , Xu Meng
Published: April 2023

Objective

To explore the effectiveness of combined immunotherapy (IT) and stereotactic radiosurgery (SRS) and address the gap between evidence-based clinical practice and academic knowledge of optimal timing of IT relative to SRS. In addition, to meet the unmet need for an up-to-date prognostic assessment model in the era of IT.

Methods

The data of 86 non-small cell lung cancer brain metastasis (NSCLCBM) patients treated with SRS to 268 brain metastases (BMs) were retrospectively extracted from our hospital database. The Kaplan–Meier analysis was employed for overall survival (OS) and a log-rank test for comparison between groups. Cox proportional hazards regression models were used to identify the significant prognostic factors. The prognostic nomogram was established utilizing the rms package of R software.

Results

IT was found to be associated with improved OS (from BM diagnosis: HR 0.363, 95% CI 0.199 - 0.661, P < 0.001; from SRS: HR 0.472, 95% CI 0.260 - 0.857, P = 0.014). Individuals who received IT in combination with SRS had better OS than those who didn’t (from the day of BM diagnosis: 16.8 vs. 8.4 months, P = 0.006; from the day of SRS: 12 vs. 7 months, P = 0.037). Peri-SRS timing of IT administration was a significant prognostic factor for OS (from BM diagnosis: HR 0.132, 95% CI 0.034 - 0.517, P = 0.004; from SRS: HR 0.14, 95% CI 0.044 - 0.450, P = 0.001). Initiating IT after SRS led to superior OS than concurrent or before (from BM diagnosis: 26.5 vs. 14.1 vs. 7.1 months; from SRS: 21.4 vs. 9.9 vs. 4.1 months, respectively). Additionally, we build a nomogram incorporating IT, cumulative intracranial tumor volume (CITV), and recursive partitioning analysis (RPA), demonstrating a remarkable prognosis prediction performance for SRS-treated NSCLCBM patients.

Conclusion

Peri-SRS IT is a promising approach in treating NSCLCBM, as improved OS was observed without significantly increasing adverse events. Receipt of IT post-SRS was associated with superior OS than those who received IT concurrently or before. Incorporating IT and CITV into the RPA index could augment its prognosis assessment value for SRS-treated NSCLCBM patients, predominantly in the wild-type.
The pre- and postoperative nomograms to predict the textbook outcomes of patients who underwent hepatectomy for hepatocellular carcinoma
Authors: Xie Gui-Lin , Liang Lei , Ye Tai-Wei , Xu Fei-Qi , Wang Dong-Dong , Xie Ya-Ming , Zhang Kang-Jun , Fu Tian-Wei , Yao Wei-Feng , Liu Jun-Wei , Zhang Cheng-Wu
Published: April 2023

Background and aims

An increasing number of studies have confirmed that non-textbook outcomes (non-TO) are a risk factor for the long-term outcome of malignant tumors. It is particularly important to identify the predictive factors of non-TO to improve the quality of surgical treatment. We attempted to construct two nomograms for preoperative and postoperative prediction of non-TO after laparoscopic hepatectomy for hepatocellular carcinoma (HCC).

Methods

Patients who underwent curative-intent hepatectomy for HCC between 2014 and 2021 at two Chinese hospitals were analyzed. Using univariate and multivariate analyses, the independent predictors of non-TO were identified. The prediction accuracy is accurately measured by the receiver operating characteristic (ROC) curve and calibration curve. ROC curves for the preoperative and postoperative models, Child–Pugh grade, BCLC staging, and 8th TNM staging were compared relative to predictive accuracy for non-TO.

Results

Among 515 patients, 286 patients (55.5%) did not achieve TO in the entire cohort. Seven and eight independent risk factors were included in the preoperative and postoperative predictive models by multivariate logistic regression analysis, respectively. The areas under the ROC curves for the postoperative and preoperative models, Child–Pugh grade, BCLC staging, and 8th TNM staging in predicting non-TO were 0.762, 0.698, 0.579, 0.569, and 0.567, respectively.

Conclusion

Our proposed preoperative and postoperative nomogram models were able to identify patients at high risk of non-TO following laparoscopic resection of HCC, which may guide clinicians to make individualized surgical decisions, improve postoperative survival, and plan adjuvant therapy against recurrence.