bluuebunny/crossref_metadata_2025 huggingface dataset:
Complications and local recurrence of chondrosarcoma and chordoma treated by total tumor resection in thoracic and lumbar spine
Authors: Liu Jiacheng , Hu Panpan , Liu Zhongjun , Wei Feng
Published: March 2024

Background

En bloc resection of spinal tumors is challenging and associated with a high incidence of complications; however, it offers the potential to reduce the risk of recurrence when a wide margin is achieved. This research aims to investigate the safety and efficacy of en bloc resection in treating thoracic and lumbar chondrosarcoma/chordoma.

Methods

Data from patients diagnosed with chondrosarcoma and chordoma in the thoracic or lumbar region, who underwent total en bloc or piecemeal resection at our institution over a 7-year period, were collected and regularly followed up. The study analyzed overall perioperative complications and compared differences in complications and local tumor recurrence between the two surgical methods.

Results

Seventeen patients were included, comprising 12 with chondrosarcoma and 5 with chordoma. Among them, 5 cases underwent intralesional piecemeal resection, while the remaining 12 underwent planned en bloc resection. The average surgical time was 684 min (sd = 287), and the mean estimated blood loss was 2300 ml (sd = 1599). Thirty-five complications were recorded, with an average of 2.06 perioperative complications per patient. 82% of patients (14/17) experienced at least one perioperative complication, and major complications occurred in 64.7% (11/17). Five patients had local recurrence during the follow-up, with a mean recurrence time of 16.2 months (sd = 7.2) and a median recurrence time of 20 months (IQR = 12.5). Hospital stays, operation time, blood loss, and complication rates did not significantly differ between the two surgical methods. The local recurrence rate after en bloc resection was lower than piecemeal resection, although not statistically significant (P = 0.067).

Conclusions

The complication rates between the two surgical procedures were similar. Considering safety and local tumor control, en bloc resection is recommended as the primary choice for patients with chondrosarcoma/chordoma in the thoracic and lumbar regions who are eligible for this treatment.
Quantitative differentiation of non-invasive bladder urothelial carcinoma and inverted papilloma based on CT urography
Authors: Jin Pengfei , Yang Liqin , Liu Yitao , Huang Jiehui , Wang Xu
Published: March 2024

Purpose

To investigate the value of CT urography (CTU) indicators in the quantitative differential diagnosis of bladder urothelial carcinoma (BUC) and inverted papilloma of the bladder (IPB).

Material and methods

The clinical and preoperative CTU imaging data of continuous 103 patients with histologically confirmed BUC or IPB were retrospectively analyzed. The imaging data included 6 qualitative indicators and 7 quantitative measures. The recorded clinical information and imaging features were subjected to univariate and multivariate logistic regression analysis to find independent risk factors for BUC, and a combined multi-indicator prediction model was constructed, and the prediction model was visualized using nomogram. ROC curve analysis was used to calculate and compare the predictive efficacy of independent risk factors and nomogram.

Results

Junction smoothness, maximum longitudinal diameter, tumor-wall interface and arterial reinforcement rate were independent risk factors for distinguishing BUC from IPB. The AUC of the combined model was 0.934 (sensitivity = 0.808, specificity = 0.920, accuracy = 0.835), and its diagnostic efficiency was higher than that of junction smoothness (AUC=0.667, sensitivity = 0.654, specificity = 0.680, accuracy = 0.660), maximum longitudinal diameter (AUC=0.757, sensitivity = 0.833, specificity = 0.604, accuracy = 0.786), tumor-wall interface (AUC=0.888, sensitivity = 0.755, specificity = 0.808, accuracy = 0.816) and Arterial reinforcement rate (AUC=0.786, sensitivity = 0.936, specificity = 0.640, accuracy = 0.864).

Conclusion

Above qualitative and quantitative indicators based on CTU and the combination of them may be helpful to the differential diagnosis of BUC and IPB, thus better assisting in clinical decision-making.

Key points

1. Bladder urothelial carcinoma (BUC) and inverted papilloma of the bladder (IPB) exhibit similar clinical symptoms and imaging presentations.

2. The diagnostic value of CT urography (CTU) in distinguishing between BUC and IPB has not been documented.

3. BUC and IPB differ in lesion size, growth pattern and blood supply.

4. The diagnostic efficiency is optimized by integrating multiple independent risk factors into the prediction model.
A solution for highly efficient electroporation of primary cytotoxic T lymphocytes
Authors: Alawar Nadia , Schirra Claudia , Hohmann Meltem , Becherer Ute
Published: March 2024

Background

Cytotoxic T lymphocytes (CTLs) are central players in the adaptive immune response. Their functional characterization and clinical research depend on efficient and reliable transfection. Although various methods have been utilized, electroporation remains the preferred technique for transient gene over-expression. However, the efficiency of electroporation is reduced for human and mouse primary CTLs. Lonza offers kits that effectively improve plasmid DNA transfection quality. Unfortunately, the removal of key components of the cell recovery medium considerably reduced the efficiency of their kit for CTLs. Our aim was to develop a new recovery medium to be used with Lonza’s Nucleofector system that would significantly enhance transfection rates.

Results

We assessed the impact of different media in which the primary CTLs were placed to recover after electroporation on cell survival, transfection rate and their ability to form an immunological synapse and to perform exocytosis. We transfected the cells with pmax-GFP and large constructs encoding for either CD81-super ecliptic pHluorin or granzyme B-pHuji. The comparison of five different media for mouse and two for human CTLs demonstrated that our new recovery medium composed of Opti-MEM-GlutaMAX supplemented with HEPES, DMSO and sodium pyruvate gave the best result in cell survival (> 50%) and transfection rate (> 30 and 20% for mouse and human cells, respectively). More importantly, the functionality of CTLs was at least twice as high as with the original Lonza recovery medium. In addition, our RM significantly improved transfection efficacy of natural killer cells that are notoriously hard to electroporate.

Conclusion

Our results show that successful transfection depends not only on the electroporation medium and pulse sequence but also on the medium applied for cell recovery. In addition, we have reduced our reliance on proprietary products by designing an effective recovery medium for both mouse and human primary CTLs and other lymphocytes that can be easily implemented by any laboratory. We expect that this recovery medium will have a significant impact on both fundamental and applied research in immunology.
Combining public datasets for automated tooth assessment in panoramic radiographs
Authors: van Nistelrooij Niels , Ghoul Khalid El , Xi Tong , Saha Anindo , Kempers Steven , Cenci Max , Loomans Bas , Flügge Tabea , van Ginneken Bram , Vinayahalingam Shankeeth
Published: March 2024

Objective

Panoramic radiographs (PRs) provide a comprehensive view of the oral and maxillofacial region and are used routinely to assess dental and osseous pathologies. Artificial intelligence (AI) can be used to improve the diagnostic accuracy of PRs compared to bitewings and periapical radiographs. This study aimed to evaluate the advantages and challenges of using publicly available datasets in dental AI research, focusing on solving the novel task of predicting tooth segmentations, FDI numbers, and tooth diagnoses, simultaneously.

Materials and methods

Datasets from the OdontoAI platform (tooth instance segmentations) and the DENTEX challenge (tooth bounding boxes with associated diagnoses) were combined to develop a two-stage AI model. The first stage implemented tooth instance segmentation with FDI numbering and extracted regions of interest around each tooth segmentation, whereafter the second stage implemented multi-label classification to detect dental caries, impacted teeth, and periapical lesions in PRs. The performance of the automated tooth segmentation algorithm was evaluated using a free-response receiver-operating-characteristics (FROC) curve and mean average precision (mAP) metrics. The diagnostic accuracy of detection and classification of dental pathology was evaluated with ROC curves and F1 and AUC metrics.

Results

The two-stage AI model achieved high accuracy in tooth segmentations with a FROC score of 0.988 and a mAP of 0.848. High accuracy was also achieved in the diagnostic classification of impacted teeth (F1 = 0.901, AUC = 0.996), whereas moderate accuracy was achieved in the diagnostic classification of deep caries (F1 = 0.683, AUC = 0.960), early caries (F1 = 0.662, AUC = 0.881), and periapical lesions (F1 = 0.603, AUC = 0.974). The model’s performance correlated positively with the quality of annotations in the used public datasets. Selected samples from the DENTEX dataset revealed cases of missing (false-negative) and incorrect (false-positive) diagnoses, which negatively influenced the performance of the AI model.

Conclusions

The use and pooling of public datasets in dental AI research can significantly accelerate the development of new AI models and enable fast exploration of novel tasks. However, standardized quality assurance is essential before using the datasets to ensure reliable outcomes and limit potential biases.
Influence of screw channel angulation on reverse torque value and fracture resistance in monolithic zirconia restorations after thermomechanical cycling: an in-vitro study
Authors: Khaledi Amir Alireza , Shalileh Shouka , Hejazi Maryam , Giti Rashin
Published: March 2024

Background

While the concept of angled screw channels has gained popularity, there remains a scarcity of research concerning the torque loss and fracture strength of monolithic zirconia restorations with various screw channel angulations when exposed to thermomechanical cycling. This in-vitro study aimed to evaluate the reverse torque value and fracture resistance of one-piece screw-retained hybrid monolithic zirconia restorations with angulated screw channels after thermomechanical cycling.

Methods

One-piece monolithic zirconia restorations, with angulated screw channels set at 0°, 15°, and 25° (n = 6 per angulation) were fabricated and bonded to titanium inserts using a dual-cure adhesive resin cement. These assemblies were then screwed to implant fixtures embedded in acrylic resin using an omnigrip screwdriver, and reverse torque values were recorded before and after thermomechanical cycles. Additionally, fracture modes were assessed subsequent to the application of compressive load. One-way ANOVA and Bonferroni post hoc test were used to compare the groups (α = 0.05).

Results

The study groups were significantly different regarding the fracture resistance (P = 0.0015), but only insignificantly different in the mean percentage torque loss (P = 0.4400). Specifically, the fracture resistance of the 15° group was insignificantly higher compared to the 0° group (P = 0.9037), but significantly higher compared to the 25° group (P = 0.0051). Furthermore, the fracture resistance of the 0° group was significantly higher than that of the 25° group (P = 0.0114).

Conclusions

One-piece hybrid monolithic zirconia restorations with angulated screw channels can be considered an acceptable choice for angulated implants in esthetic areas, providing satisfactory fracture strength and torque loss.
Exploring risk factors of pelvic organ prolapse at eastern of Democratic Republic of Congo: a case-control study
Authors: Ilunga-Mbaya Eloge , Mukwege Denis , De Tayrac Renaud , Mbunga Branly , Maroyi Raha , Ntakwinja Mukanire , Sengeyi Mushengezi Amani Dieudonné
Published: March 2024

Background

Pelvic organ prolapse is a common debilitating condition worldwide. Despite surgical treatment, its recurrence can reach up to 30%. It has multiple risk factors, some of which are particular for a low-resource settings. The identification these factors would help to devise risk models allowing the development of prevention policies. The objective of this study was to explore risk factors for pelvic organ prolapse in a population in eastern Democratic Republic of Congo (DRC).

Methods

This was an unmatched case-control study conducted between January 2021 and January 2022. The sample size was estimated to be a total of 434 women (217 with prolapse as cases and 217 without prolapse as controls). Data comparisons were made using the Chi-Square and Student T tests. Binary and multivariate logistic regressions were used to determine associated factors. A p < 0.05 was considered significant.

Results

Variables identified as definitive predictors of pelvic organ prolapse included low BMI (aOR 2.991; CI 1.419–6.307; p = 0.004), home birth (aOR 6.102; CI 3.526–10.561; p < 0.001), family history of POP (aOR 2.085; CI 1.107–3.924; p = 0.023), history of birth without an episiotomy (aOR 3.504; CI 2.031–6.048; p = 0), height ≤ 150 cm (aOR 5.328; CI 2.942–9.648; p < 0.001) and history of giving birth to a macrosomic baby (aOR 1.929; IC 1.121–3.321; p = 0.018).

Conclusions

This study identified that Body Mass Index and birth-related factors are definitive predictors of pelvic organ prolapse in a low-resource setting. These factors are potentially modifiable and should be targeted in any future pelvic organ prolapse prevention policy. Additionally, there seems to be a genetic predisposition for prolapse, which warrants further assessment in specifically designed large scale studies.
Tumoricidal properties of thymoquinone on human colorectal adenocarcinoma cells via the modulation of autophagy
Authors: Moulana Mohammad Saleh , Haiaty Sanya , Bazmani Ahad , Shabkhizan Roya , Moslehian Marziyeh Sadat , Sadeghsoltani Fatemeh , Mostafazadeh Mostafa , Asadi Mohammad Reza , Talebi Mehdi , Jafari Zahra , Morovati Mohammad Reza , Farzaei Mohammad Hosein , Rahbarghazi Reza
Published: March 2024

Colorectal cancer (CRC) is deadly anaplastic changes in the gastrointestinal tract with high-rate mortality. In recent years, the application of phytocompounds has been extended along with different therapeutic protocols. Here, we monitored the effects of Thymoquinone (TQ) on autophagy via mitochondrial function after modulation of the Wnt/β-catenin signaling pathway.

Human colorectal adenocarcinoma HT-29 cells were treated with TQ (60 µM) and 15 µM Wnt3a inhibitor (LGK974) for 48 h. The survival rate was evaluated using an MTT assay. The expression of Wnt-related factors (c-Myc, and Axin), angiogenesis (VE-Cadherin), and mitophagy-related factors (PINK1, OPTN) was assessed using real-time PCR assay. Protein levels of autophagy factors (Beclin-1, LC3, and P62) were monitored using western blotting. Using flow cytometry analysis, the intracellular accumulation of Rhodamine 123 was evaluated. The migration properties were analyzed using a scratch wound healing assay.

Data indicated that TQ can reduce the viability of HT-29 cells compared to the control cells (p < 0.05). The expression of VE-Cadherin was inhibited while the expression of PINK1 was induced in treated cells (p < 0.05). Both LGK974 and TQ-treated cells exhibited activation of autophagy flux (Beclin-1↑, LC3II/I↑, and p62↓) compared to the control group (p < 0.05). TQ can increase intracellular accumulation of Rhodamine 123, indicating the inhibition of efflux mechanisms in cancer cells. Along with these changes, the migration of cells was also reduced (p < 0.05).

TQ is a potential phytocompound to alter the dynamic growth of human colorectal HT-29 cells via the modulation of autophagy, and mitophagy-related mechanisms.
Consensus on relevant point-of-care ultrasound skills in General Practice: a two-round French Delphi study
Authors: Camard Louis , Liard Roxane , Duverne Sophie , Ibanez Gladys , Skendi Mariela
Published: March 2024

Context

Point-of-Care Ultrasound (POCUS) has become an important tool in the clinical practice of many specialties, but its use and impact in General Practice in France remains to be explored.

Objective

The objective of this study is to obtain a consensus among experienced French general practitioners on a list of relevant POCUS skills in General Practice in 4 anatomical regions.

Method

We used a two-round Delphi method to obtain a consensus. An initial list of skills was drawn by conducting a literature review. To rate each skill, we used a nine-point Likert scale. An interactive meeting between experts took place between Delphi rounds. POCUS experts in General Practice were defined as general practitioners with theoretical training in ultrasound who regularly perform ultrasound, who have performed ultrasound for more than five years and/or are involved in providing ultrasound training.

Results

11 French general practitioners screened 83 skills in 4 anatomical regions: abdominal, urogenital, vascular, gynecology and obstetrics. An agreement was obtained for 36 POCUS skills as to their appropriateness in General Practice. There were 17 skills with a strong appropriate agreement (100% of “7–9” ratings) and 19 skills with a relative agreement (100% of “5–9” ratings).

Conclusion

These skills could serve as a basis for guidelines on the use and curriculum of POCUS in General Practice in France as well as in other countries with similar healthcare systems.
The effect of “typical case discussion and scenario simulation” on the critical thinking of midwifery students: Evidence from China
Authors: Wang Yuji , Peng Yijuan , Huang Yan
Published: March 2024

Background

Assessment ability lies at the core of midwives’ capacity to judge and treat clinical problems effectively. Influenced by the traditional teaching method of “teacher-led and content-based”, that teachers involve imparting a large amount of knowledge to students and students lack active thinking and active practice, the clinical assessment ability of midwifery students in China is mostly at a medium or low level. Improving clinical assessment ability of midwifery students, especially critical thinking, is highly important in practical midwifery education. Therefore, we implemented a new teaching program, “typical case discussion and scenario simulation”, in the Midwifery Health Assessment course. Guided by typical cases, students were organized to actively participate in typical case discussions and to promote active thinking and were encouraged to practice actively through scenario simulation. In this study, we aimed to evaluate the effect of this strategy on the critical thinking ability of midwifery students.

Method

A total of 104 midwifery students in grades 16–19 at the West China School of Nursing, Sichuan University, were included as participants through convenience sampling. All the students completed the Midwifery Health Assessment course in the third year of university. Students in grades 16 and 17 were assigned to the control group, which received routine teaching in the Midwifery Health Assessment, while students in grades 18 and 19 were assigned to the experimental group, for which the “typical case discussion and scenario simulation” teaching mode was employed. The Critical Thinking Disposition Inventory-Chinese Version (CTDI-CV) and Midwifery Health Assessment Course Satisfaction Questionnaire were administered after the intervention.

Results

After the intervention, the critical thinking ability of the experimental group was greater than that of the control group (284.81 ± 27.98 and 300.94 ± 31.67, p = 0.008). Furthermore, the experimental group exhibited higher scores on the four dimensions of Open-Mindedness (40.56 ± 5.60 and 43.59 ± 4.90, p = 0.005), Analyticity (42.83 ± 5.17 and 45.42 ± 5.72, p = 0.020), Systematicity (38.79 ± 4.70 and 41.88 ± 6.11, p = 0.006), and Critical Thinking Self-Confidence (41.35 ± 5.92 and 43.83 ± 5.89, p = 0.039) than did the control group. The course satisfaction exhibited by the experimental group was greater than that exhibited by the control group (84.81 ± 8.49 and 90.19 ± 8.41, p = 0.002).

Conclusion

The “typical case discussion and scenario simulation” class mode can improve the critical thinking ability of midwifery students and enhance their curriculum satisfaction. This approach carries a certain degree of promotional significance in medical education.
A phase II study of belumosudil for chronic graft-versus-host disease in patients who failed at least one line of systemic therapy in China
Authors: Wang Ying , Wu Depei , Zhang Xiang , Li Yuhua , He Yanjie , Liu Qifa , Xuan Li , Li Zhenyu , Qi Kunming , Sun Yuqian , Wang Shunqing , Mo Wenjian , Gao Lei , Hua Ye , Wang Yu , Zhang Ying
Published: March 2024

Background

Chronic graft-versus-host disease (cGVHD) is an immune-related disorder that is the most common complication post-allogenic hematopoietic stem cell transplant. Corticosteroids with or without calcineurin inhibitors (CNIs) remain the mainstay of cGVHD treatment for first-line therapy. However, for many patients, cGVHD symptoms cannot be effectively managed and thus require second-line therapy. Currently, there is no approved treatment for second-line cGVHD treatment in China. In this study, belumosudil, a highly selective and potent rho-associated coiled-coil-containing protein kinase-2 inhibitor demonstrated to be effective for cGVHD in the United States and other Western countries, is investigated in patients with cGVHD in China for its overall benefit–risk balance.

Methods

This multicenter, open-label phase II study evaluated the safety, efficacy, and pharmacokinetics of oral belumosudil 200 mg once daily in cGVHD patients who had been treated with at least one line of systemic therapy in China. The primary endpoint was overall response rate (ORR); each individual patient’s response was assessed by the investigator using the 2014 National Institutes of Health consensus criteria. Secondary endpoints were duration of response (DOR), time to response (TTR), changes in Lee Symptom Scale (LSS) score, organ response rate, corticosteroid dose change, CNI dose change, failure-free survival, time-to-next-treatment, overall survival, and safety.

Results

Thirty patients were enrolled in the study with a median follow-up time of 12.9 months. ORR was 73.3% (95% confidence interval: 54.1–87.7%) and all responders achieved partial response. Median DOR among responders was not reached and median TTR was 4.3 weeks (range: 3.9–48.1). Fifteen patients (50.0%) achieved clinically meaningful response in terms of reduction in LSS score by ≥ 7 points from baseline. Corticosteroid and CNI dose reductions were reported in 56.7% (17/30) and 35.0% (7/20) of patients, respectively. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity, with 11 patients (36.7%) experiencing grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAE was pneumonia (n = 5, 16.7%).

Conclusions

Belumosudil treatment demonstrated a favorable benefit–risk balance in treating cGVHD patients who previously have had standard corticosteroid therapy in China where approved second-line setting is absent.

Trial registration

ClinicalTrials.gov identifier NCT04930562.
Rapid assessment of the blood-feeding histories of wild-caught malaria mosquitoes using mid-infrared spectroscopy and machine learning
Authors: Mwanga Emmanuel P. , Mchola Idrisa S. , Makala Faraja E. , Mshani Issa H. , Siria Doreen J. , Mwinyi Sophia H. , Abbasi Said , Seleman Godian , Mgaya Jacqueline N. , Jiménez Mario González , Wynne Klaas , Sikulu-Lord Maggy T. , Selvaraj Prashanth , Okumu Fredros O. , Baldini Francesco , Babayan Simon A.
Published: March 2024

Background

The degree to which Anopheles mosquitoes prefer biting humans over other vertebrate hosts, i.e. the human blood index (HBI), is a crucial parameter for assessing malaria transmission risk. However, existing techniques for identifying mosquito blood meals are demanding in terms of time and effort, involve costly reagents, and are prone to inaccuracies due to factors such as cross-reactivity with other antigens or partially digested blood meals in the mosquito gut. This study demonstrates the first field application of mid-infrared spectroscopy and machine learning (MIRS-ML), to rapidly assess the blood-feeding histories of malaria vectors, with direct comparison to PCR assays.

Methods and results

Female Anopheles funestus mosquitoes (N = 1854) were collected from rural Tanzania and desiccated then scanned with an attenuated total reflectance Fourier-transform Infrared (ATR-FTIR) spectrometer. Blood meals were confirmed by PCR, establishing the ‘ground truth’ for machine learning algorithms. Logistic regression and multi-layer perceptron classifiers were employed to identify blood meal sources, achieving accuracies of 88%–90%, respectively, as well as HBI estimates aligning well with the PCR-based standard HBI.

Conclusions

This research provides evidence of MIRS-ML effectiveness in classifying blood meals in wild Anopheles funestus, as a potential complementary surveillance tool in settings where conventional molecular techniques are impractical. The cost-effectiveness, simplicity, and scalability of MIRS-ML, along with its generalizability, outweigh minor gaps in HBI estimation. Since this approach has already been demonstrated for measuring other entomological and parasitological indicators of malaria, the validation in this study broadens its range of use cases, positioning it as an integrated system for estimating pathogen transmission risk and evaluating the impact of interventions.
Survival in pregnancy-associated breast cancer patients compared to non-pregnant controls
Authors: Martín Cameán María , Jaunarena Ibon , Sánchez-Méndez Jose Ignacio , Martín Covadonga , Boria Félix , Martín Elena , Spagnolo Emanuela , Zapardiel Ignacio , Hernández Gutiérrez Alicia
Published: March 2024

Background

Pregnancy-associated breast cancer (PABC) is a rare entity whose prognosis has previously been studied and is subject to controversy.

Methods

Survival of patients with PABC diagnosed between 2009 and 2021 with breast cancer during pregnancy or until 1 year after childbirth was compared with non-pregnant patients with breast cancer from the same period at La Paz University Hospital. Cox proportional hazards regression was used to compare disease-free (DFS) and overall (OS) survival between the groups, adjusting for grade and pathologic stage.

Results

Among the 89 included patients with breast cancer, 34 were diagnosed during pregnancy, and 55 were not pregnant. The pregnant patients were more likely to have grade 3 tumors (61.3% vs 37%, p = 0.023) and an advanced stage (pathologic stage III-IV: 44.1% vs 17.6%, p = 0.008). Median follow-up was 47 months for the pregnant group and 46 months for the control group. After adjustments for tumor grade and pathologic stage, OS was comparable between the groups (HR 2.03; 95% CI 0.61 to 6.79; P = 0.25).

Conclusions

The outcome of women diagnosed with PABC is comparable to young non-pregnant controls. However, it should be taken into account that PABC has a more aggressive phenotype.
Cost-utility analysis of TAVI compared with surgery in patients with severe aortic stenosis at low risk of surgical mortality in the Netherlands
Authors: Eerdekens Rob , Kats Suzanne , Grutters Janneke PC , Green Michelle , Shore Judith , Candolfi Pascal , Oortwijn Wija , Harst Pim Van Der , Tonino Pim
Published: March 2024

Background

There is growing evidence to support the benefits of transcatheter aortic valve implantation (TAVI) over surgical aortic valve replacement (SAVR) in patients with symptomatic severe aortic stenosis (sSAS) who are at high- or intermediate-risk of surgical mortality. The PARTNER 3 trial showed clinical benefits with SAPIEN 3 TAVI compared with SAVR in patients at low risk of surgical mortality. Whether TAVI is also cost-effective compared with SAVR for low-risk patients in the Dutch healthcare system remains uncertain. This article presents an analysis using PARTNER 3 outcomes and costs data from the Netherlands to inform a cost-utility model and examine cost implications of TAVI over SAVR in a Dutch low-risk population.

Methods

A two-stage cost-utility analysis was performed using a published and validated health economic model based on adverse events with both TAVI and SAVR interventions from a published randomized low risk trial dataset, and a Markov model that captured lifetime healthcare costs and patient outcomes post-intervention. The model was adapted using Netherlands-specific cost data to assess the cost-effectiveness of TAVI and SAVR. Uncertainty was addressed using deterministic and probabilistic sensitivity analyses.

Results

TAVI generated 0.89 additional quality-adjusted life years (QALYs) at a €4742 increase in costs per patient compared with SAVR over a lifetime time horizon, representing an incremental cost-effectiveness ratio (ICER) of €5346 per QALY gained. Sensitivity analyses confirm robust results, with TAVI remaining cost-effective across several sensitivity analyses.

Conclusions

Based on the model results, compared with SAVR, TAVI with SAPIEN 3 appears cost-effective for the treatment of Dutch patients with sSAS who are at low risk of surgical mortality. Qualitative data suggest broader societal benefits are likely and these findings could be used to optimize appropriate intervention selection for this patient population.
Dihydromyricetin ameliorates hepatic steatosis and insulin resistance via AMPK/PGC-1α and PPARα-mediated autophagy pathway
Authors: Yang Yan , Qiu Wen , Xiao Jiyuan , Sun Jie , Ren Xuan , Jiang Luxia
Published: March 2024

Background

Dihydromyricetin (DHM), a flavonoid compound of natural origin, has been identified in high concentrations in ampelopsis grossedentata and has a broad spectrum of biological and pharmacological functions, particularly in regulating glucose and lipid metabolism. The objective of this research was to examine how DHM affected nonalcoholic fatty liver disease (NAFLD) and its underlying mechanisms involved in the progression of NAFLD in a rat model subjected to a high-fat diet (HFD). Additionally, the study examines the underlying mechanisms in a cellular model of steatohepatitis using palmitic acid (PA)-treated HepG2 cells, with a focus on the potential correlation between autophagy and hepatic insulin resistance (IR) in the progress of NAFLD.

Methods

SD rats were exposed to a HFD for a period of eight weeks, followed by a treatment with DHM (at doses of 50, 100, and 200 mg·kg−1·d−1) for additional six weeks. The HepG2 cells received a 0.5 mM PA treatment for 24 h, either alone or in conjunction with DHM (10 µM). The histopathological alterations were assessed by the use of Hematoxylin–eosin (H&E) staining. The quantification of glycogen content and lipid buildup in the liver was conducted by the use of PAS and Oil Red O staining techniques. Serum lipid and liver enzyme levels were also measured. Autophagic vesicle and autolysosome morphology was studied using electron microscopy. RT-qPCR and/or western blotting techniques were used to measure IR- and autophagy-related factors levels.

Results

The administration of DHM demonstrated efficacy in ameliorating hepatic steatosis, as seen in both in vivo and in vitro experimental models. Moreover, DHM administration significantly increased GLUT2 expression, decreased G6Pase and PEPCK expression, and improved IR in the hepatic tissue of rats fed a HFD and in cells exhibiting steatosis. DHM treatment elevated Beclin 1, ATG 5, and LC3-II levels in hepatic steatosis models, correlating with autolysosome formation. The expression of AMPK levels and its downstream target PGC-1α, and PPARα were decreased in HFD-fed rats and PA-treated hepatocytes, which were reversed through DHM treatment. AMPK/ PGC-1α and PPARα knockdown reduced the impact of DHM on hepatic autophagy, IR and accumulation of hepatic lipid.

Conclusions

Our findings revealed that AMPK/ PGC-1α, PPARα-dependent autophagy pathways in the pathophysiology of IR and hepatic steatosis has been shown, suggesting that DHM might potentially serve as a promising treatment option for addressing this disease.

Graphical Abstract
Single-cell RNA sequencing reveals the immune features and viral tropism in the central nervous system of mice infected with Japanese encephalitis virus
Authors: Yang Ling’en , Xiong Junyao , Liu Yixin , Liu Yinguang , Wang Xugang , Si Youhui , Zhu Bibo , Chen Huanchun , Cao Shengbo , Ye Jing
Published: March 2024

Japanese encephalitis virus (JEV) is a neurotropic pathogen that causes lethal encephalitis. The high susceptibility and massive proliferation of JEV in neurons lead to extensive neuronal damage and inflammation within the central nervous system. Despite extensive research on JEV pathogenesis, the effect of JEV on the cellular composition and viral tropism towards distinct neuronal subtypes in the brain is still not well comprehended. To address these issues, we performed single-cell RNA sequencing (scRNA-seq) on cells isolated from the JEV-highly infected regions of mouse brain. We obtained 88,000 single cells and identified 34 clusters representing 10 major cell types. The scRNA-seq results revealed an increasing amount of activated microglia cells and infiltrating immune cells, including monocytes & macrophages, T cells, and natural killer cells, which were associated with the severity of symptoms. Additionally, we observed enhanced communication between individual cells and significant ligand-receptor pairs related to tight junctions, chemokines and antigen-presenting molecules upon JEV infection, suggesting an upregulation of endothelial permeability, inflammation and antiviral response. Moreover, we identified that Baiap2-positive neurons were highly susceptible to JEV. Our findings provide valuable clues for understanding the mechanism of JEV induced neuro-damage and inflammation as well as developing therapies for Japanese encephalitis.
Role of aquaporin-4 polarization in extracellular solute clearance
Authors: Bojarskaite Laura , Nafari Sahar , Ravnanger Anne Katrine , Frey Mina Martine , Skauli Nadia , Åbjørsbråten Knut Sindre , Roth Lena Catherine , Amiry-Moghaddam Mahmood , Nagelhus Erlend A. , Ottersen Ole Petter , Bogen Inger Lise , Thoren Anna E. , Enger Rune
Published: March 2024

Waste from the brain has been shown to be cleared via the perivascular spaces through the so-called glymphatic system. According to this model the cerebrospinal fluid (CSF) enters the brain in perivascular spaces of arteries, crosses the astrocyte endfoot layer, flows through the parenchyma collecting waste that is subsequently drained along veins. Glymphatic clearance is dependent on astrocytic aquaporin-4 (AQP4) water channels that are highly enriched in the endfeet. Even though the polarized expression of AQP4 in endfeet is thought to be of crucial importance for glymphatic CSF influx, its role in extracellular solute clearance has only been evaluated using non-quantitative fluorescence measurements. Here we have quantitatively evaluated clearance of intrastriatally infused small and large radioactively labeled solutes in mice lacking AQP4 (Aqp4–/–) or lacking the endfoot pool of AQP4 (Snta1–/–). We confirm that Aqp4–/– mice show reduced clearance of both small and large extracellular solutes. Moreover, we find that the Snta1–/– mice have reduced clearance only for the 500 kDa [3H]dextran, but not 0.18 kDa [3H]mannitol suggesting that polarization of AQP4 to the endfeet is primarily important for clearance of large, but not small molecules. Lastly, we observed that clearance of 500 kDa [3H]dextran increased with age in adult mice. Based on our quantitative measurements, we confirm that presence of AQP4 is important for clearance of extracellular solutes, while the perivascular AQP4 localization seems to have a greater impact on clearance of large versus small molecules.
Which roads lead to access? A global landscape of six COVID-19 vaccine innovation models
Authors: Alonso Ruiz Adrián , Bezruki Anna , Shinabargar Erika , Large Kaitlin , Vieira Marcela , Slovenski Iulia , Liu Yiqi , Agarwal Surabhi , Becker Anna , Moon Suerie
Published: March 2024

Background

Unequal and inequitable access to Covid-19 vaccines in low- and middle-income countries (L&MICs) was a major political, ethical and public health failure in the pandemic. However, vaccine developers’ practices were not monolithic, but rather, took diverse approaches to supplying different countries, with important implications for global access.

Results

Using data on R&D investments, regulatory approvals, manufacturing and purchase agreements, and vaccine deliveries, we identified six distinct innovation models that apply across the 14 COVID-19 vaccines with more international presence from 2020–2022. “Western Early Arrivers” Pfizer/BioNTech and Moderna supplied the largest volumes quickly and prioritized high-income countries (HICs) from registration to vaccine delivery. “Western Latecomers” Janssen and Novavax supplied intermediate volumes later, also prioritizing HICs but with a greater proportion to L&MICs. “Major Chinese Developers” Sinopharm and Sinovac supplied intermediate volumes early, primarily to middle-income countries (MICs). “Russian Developer” Gamaleya completed development early but ultimately supplied small volumes, primarily to middle-income countries (MICs). “Cosmopolitan Developer” Oxford/AstraZeneca supplied large volumes early to HICs and MICs at the lowest prices. Finally, “Small MIC Developers” CanSino, Bharat Biotech, Medigen, Finlay Institute and the Center for Genetic Engineering and Biotechnology (CGEB), exported relatively small volumes to a few MICs. Low-income countries (LICs) were not targeted by any developer, and received far fewer doses, later, than any other income group. Almost all developers received public funding and other forms of support, but we found little evidence that such support was leveraged to expand global access.

Conclusions

Each of the six innovation models has different implications for which countries get access to which vaccines, how quickly, and at which prices. Each offers different strengths and weaknesses for achieving equitable access. Our findings also suggest that Western firms had the greatest capacity to develop and deliver vaccines quickly during the pandemic, but such capacity is rapidly becoming more globally distributed with MICs playing a significant role, especially in supplying other MICs. Given the critical role of public support in enabling pandemic vaccine development and supply, governments have both the capacity and responsibility to craft international rules that will make responses to future pandemics more equitable and effective.
Sub-coronary aortic root replacement post-aortic valve dehiscence: a case report
Authors: Divya Aabha , Mangel Tobin , Seetharaman Rakesh , Taghavi John Fouad
Published: March 2024

This is a case report of a 78-year-old male who underwent a sub-coronary aortic valve and root replacement due to valve dehiscence and aortic root pseudoaneurysm. The patient had complex anomalous coronary anatomy and had undergone a previous tissue aortic valve replacement in 2013. The patient made an uneventful recovery and was discharged from the hospital five days later. The authors suggest that the sub-coronary root replacement technique should be considered in elderly patients and patients with complex coronary anatomy.
Moderate- to vigorous-intensity physical activities for hemophilia A patients during low-dose pharmacokinetic-guided extended half-life factor VIII prophylaxis
Authors: Srichumpuang Chonlatis , Rakmanotham Arunothai , Moonla Chatphatai , Sosothikul Darintr
Published: March 2024

Background

Low-dose pharmacokinetic (PK)-guided extended half-life (EHL) factor VIII (FVIII) prophylaxis can reduce the bleeding risk in hemophilia A (HA) patients. An increase in physical activities for promoting musculoskeletal health may enhance the benefits of prophylactic therapy.

Objectives

To determine the clinical impact of moderate- to vigorous-intensity physical activities in HA patients during low-dose PK-guided EHL FVIII prophylaxis.

Patients/Methods

This prospective study enrolled patients with moderate/severe HA (baseline FVIII levels ≤ 5 IU/dL) who had received low-dose PK-guided EHL FVIII prophylaxis for ≥ 6 months. An individualized exercise protocol was introduced to each participant, targeting a 65% increase in the maximum predicted heart rate for ≥ 150 min/week, while continuing low-dose PK-guided EHL FVIII prophylaxis for 6 months. Before and after implementing the intervention, annualized bleeding rates (ABR), annualized joint bleeding rates (AJBR), Hemophilia Joint Health Scores (HJHS), skeletal muscle mass, hemophilia-specific quality-of-life (QoL) scores and annualized FVIII consumption were compared.

Results

Of 13 participants (mean age ± standard deviation [SD]: 20.1 ± 6.8 years), ABR, AJBR, and HJHS were significantly reduced (mean differences [MD] ± SD: −5.7 ± 2.6 bleeds/year, −4.2 ± 2.6 joint bleeds/year, and −4.3 ± 3.2 marks, respectively; P < 0.05) after applying the 6-month exercise protocol. Skeletal muscle mass and QoL scores had also improved (P = 0.001), while FVIII usage had decreased (MD ± SD: −129.1 ± 208.7 IU/kg/year; P < 0.05).

Conclusions

The combination of moderate- to vigorous-intensity physical activities with low-dose PK-guided EHL FVIII prophylaxis improves bleeding prevention, musculoskeletal status and QoL in patients with moderate/severe HA. By minimizing FVIII consumption, this strategy helps optimize hemophilia care in countries with budget constraints. ClinicalTrials.gov NCT05728528.
Caregiver perspectives on patient-focused drug development for Phelan-McDermid syndrome
Authors: Gizzo Luciana , Bliss Geraldine , Palaty Chrystal , Kolevzon Alexander
Published: March 2024

Background

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by SHANK3 haploinsufficiency with clinical manifestations that can be devastating and profoundly affect quality of life.

Results

The Externally Led Patient-Focused Drug Development (EL-PFDD) meeting was an opportunity for families affected by PMS to share with the Food and Drug Administration (FDA) how symptoms impact their lives and how treatments could be most meaningful. The Voice of the Patient report serves as a summary of this meeting to influence upcoming drug development and clinical trials. The purpose of this report is to provide a clinical perspective on the results of the EL-PFDD meeting to amplify the voice of these caregivers to the scientific community.

Conclusions

Caregivers prioritize an improved quality of life for their loved ones characterized by improved cognitive function, improved communication, increased independence, and reduced risk of regression. With these caregiver priorities in mind, this report provides the FDA and the scientific community with a clear understanding of which aspects of PMS should influence the development of future therapeutics.
Temporal changes in mammographic breast density and breast cancer risk among women with benign breast disease
Authors: Mullooly Maeve , Fan Shaoqi , Pfeiffer Ruth M. , Bowles Erin Aiello , Duggan Máire A. , Falk Roni T. , Richert-Boe Kathryn , Glass Andrew G. , Kimes Teresa M. , Figueroa Jonine D. , Rohan Thomas E. , Abubakar Mustapha , Gierach Gretchen L.
Published: March 2024

Introduction

Benign breast disease (BBD) and high mammographic breast density (MBD) are prevalent and independent risk factors for invasive breast cancer. It has been suggested that temporal changes in MBD may impact future invasive breast cancer risk, but this has not been studied among women with BBD.

Methods

We undertook a nested case–control study within a cohort of 15,395 women with BBD in Kaiser Permanente Northwest (KPNW; 1970–2012, followed through mid-2015). Cases (n = 261) developed invasive breast cancer > 1 year after BBD diagnosis, whereas controls (n = 249) did not have breast cancer by the case diagnosis date. Cases and controls were individually matched on BBD diagnosis age and plan membership duration. Standardized %MBD change (per 2 years), categorized as stable/any increase (≥ 0%), minimal decrease of less than 5% or a decrease greater than or equal to 5%, was determined from baseline and follow-up mammograms. Associations between MBD change and breast cancer risk were examined using adjusted unconditional logistic regression.

Results

Overall, 64.5% (n = 329) of BBD patients had non-proliferative and 35.5% (n = 181) had proliferative disease with/without atypia. Women with an MBD decrease (≤ − 5%) were less likely to develop breast cancer (Odds Ratio (OR) 0.64; 95% Confidence Interval (CI) 0.38, 1.07) compared with women with minimal decreases. Associations were stronger among women ≥ 50 years at BBD diagnosis (OR 0.48; 95% CI 0.25, 0.92) and with proliferative BBD (OR 0.32; 95% CI 0.11, 0.99).

Discussion

Assessment of temporal MBD changes may inform risk monitoring among women with BBD, and strategies to actively reduce MBD may help decrease future breast cancer risk.
Clinical statistical analysis plan for the ACCURE trial: the effect of appendectomy on the clinical course of ulcerative colitis, a randomised international multicentre trial
Authors: Visser Eva , Heuthorst Lianne , Pathmakanthan Shri , Bemelman Willem A. , D’Haens Geert R. , Handley Kelly , Fakis Apostolos , Pinkney Thomas D. , Buskens Christianne J. , Dijkgraaf Marcel G. W.
Published: March 2024

Background

The primary treatment of ulcerative colitis (UC) is medical therapy using a standard step-up approach. An appendectomy might modulate the clinical course of UC, decreasing the incidence of relapses and reducing need for medication. The objective of the ACCURE trial is to assess the efficacy of laparoscopic appendectomy in addition to standard medical treatment in maintaining remission in UC patients. This article presents the statistical analysis plan to evaluate the outcomes of the ACCURE trial.

Design and methods

The ACCURE trial was designed as a multicentre, randomised controlled trial. UC patients with a new diagnosis or a disease relapse within the past 12 months, treated with 5-ASA, corticosteroids, or immunomodulators until complete clinical and endoscopic remission (defined as total Mayo score < 3 with endoscopic subscore of 0 or 1), were counselled for inclusion. Also, patients previously treated with biologicals who had a washout period of at least 3 months were considered for inclusion. Patients were randomised (1:1) to laparoscopic appendectomy plus maintenance treatment or a control group (maintenance therapy only). The primary outcome is the 1-year UC relapse rate (defined as a total Mayo-score ≥ 5 with endoscopic subscore of 2 or 3, or clinically as an exacerbation of symptoms and rectal bleeding or FCP > 150 or intensified medical therapy other than 5-ASA therapy). Secondary outcomes include number of relapses per patient, time to first relapse, disease activity, number of colectomies, medication usage, and health-related quality of life.

Discussion

The ACCURE trial will provide comprehensive evidence whether adding an appendectomy to maintenance treatment is superior to maintenance treatment only in maintaining remission in UC patients.

Trial registration

Dutch Trial Register (NTR) NTR2883. Registered May 3, 2011. ISRCTN, ISRCTN60945764. Registered August 12, 2019.