bluuebunny/crossref_metadata_2025 huggingface dataset:
Isokinetic training of lower extremity during the early stage promote functional restoration in elder patients with disability after Total knee replacement (TKR) - a randomized control trial
Authors: Cheng Yuan-Yang , Chen Cheng-Hsu , Wang Shun-Ping
Published: February 2024

Background

Transient progressive weakness and disability of lower limb during the early stage after TKR will increase the risk of fall, but the superior postoperative strength training mode have not been elucidated for functional restoration. This study aimed to compare whether the isokinetic lower limb training is superior to either isotonic or home isometric exercise during early stage after TKR in older people.

Methods

A total of 43 recruited old participants (mean age, 68.40 years old) receiving TKR were divided randomly based on the different four-week training modes into three groups including isokinetic, isotonic, and home isometric exercise (control group). The primary outcome was set as functional performance in terms of Timed Up and Go (TUG) test and the secondary outcomes include the peak torque of knee at 60 and 120 degree/ second, Short-Form 36 Health Survey (SF-36), and Western Ontario and McMaster Universities Arthritis index (WOMAC).

Results

All of the peak torque measurements of the knee improved significantly in both the isokinetic and the isotonic group, but not in the control group. Although isotonic training resulted in more strength gains, a significant enhancement in TUG test was observed in the isokinetic group only (p = 0.003). However, there were no significantly improvement of TUG test after training in other two groups. SF-36 and WOMAC improved after training in all three groups, with no significant difference in the degree of improvement between groups.

Conclusion

Isokinetic training for 4 weeks following TKR effectively improved all the outcome parameters in this study, including the TUG test, lower limb strength, and functional scores. However, both isokinetic and isotonic training modes could be recommended after TKR because of no significant difference in the degree of improvement between these two groups.

Trial registration

Clinical trial registration number: NCT02938416.

Level of evidence

I
The effect of a treatment switch to integrase Strand transfer inhibitor–based regimens on weight gain and other metabolic syndrome-related conditions
Authors: Maman Omer , Ahmad Wiessam Abu , Perzon Ofer , Mahlab-Guri Keren , Elbirt Daniel , Elinav Hila
Published: February 2024

Objective

This study aimed to assess weight gain associated with treatment switching to INSTI-based regimens in people living with HIV (PLWH) and to determine whether it is accompanied by worsening features of hypertension, dyslipidemia, or hyperglycemia.

Methods

In this two-center retrospective observational study, we assessed weight gain and metabolic features in PLWH who switched to an INSTI-based regimen (study group) as compared to patients who remained on a non-INSTI regimen (control group) over a 24-month follow-up period.

Results

One-hundred seventy-four PLWH were included in the study group, and 175 were included in the control group. The study group gained 2.51 kg ± 0.31 (mean ± standard deviation) over the 2 years of follow-up, while the control group gained 1.1 ± 0.31 kg over the same time course (p < 0.001). INSTI treatment, Caucasian origin, and lower BMI were risk factors associated with excessive weight gain during the 2 years of follow-up. Among metabolic parameters, only glucose levels increased after initiating INSTI-based regimens, although limited to males of African origin (p = 0.009).

Conclusions

We observed a mild weight gain after switching to INSTI-based regimens, with no major impact on metabolic parameters over 2 years of follow-up. Longer follow-up might be needed to observe the adverse metabolic effects of INSTI-based regimens. The impact on weight gain should be discussed with every patient before the treatment switch to ensure a balanced diet and physical activity to prevent excessive weight gain that might hamper compliance with ART.
p90RSK pathway inhibition synergizes with cisplatin in TMEM16A overexpressing head and neck cancer
Authors: Yassin-Kassab Abdulkader , Chatterjee Suman , Khan Nayel , Wang Nathaniel , Sandulache Vlad C. , Huang Eric H-B. , Burns Timothy F. , Duvvuri Umamaheswar
Published: February 2024

Head and neck squamous cell carcinoma (HNSCC) constitutes one of the most common types of human cancers and often metastasizes to lymph nodes. Platinum-based chemotherapeutic drugs are commonly used for treatment of a wide range of cancers, including HNSCC. Its mode of action relies on its ability to impede DNA repair mechanisms, inducing apoptosis in cancer cells. However, due to acquired resistance and toxic side-effects, researchers have been focusing on developing novel combinational therapeutic strategies to overcome cisplatin resistance. In the current study, we identified p90RSK, an ERK1/2 downstream target, as a key mediator and a targetable signaling node against cisplatin resistance. Our results strongly support the role of p90RSK in cisplatin resistance and identify the combination of p90RSK inhibitor, BI-D1870, with cisplatin as a novel therapeutic strategy to overcome cisplatin resistance. In addition, we have identified TMEM16A expression as a potential upstream regulator of p90RSK through the ERK pathway and a biomarker of response to p90RSK targeted therapy in the context of cisplatin resistance.
Quantitative evaluation of ocular vascularity and correlation analysis in patients with diabetic retinopathy by SMI and OCTA
Authors: Wei Jin , Chen Chong , Shen Yinchen , Li Fang , Yiyang Shu , Liu Haiyun
Published: February 2024

Aims

To find potential relation between retrobulbar vessels and fundus microvessels and to detect sensitive and effective clinical indicators in predicting the progress of diabetic retinopathy (DR), ocular hemodynamics were measured using superb microvascular imaging (SMI) and ultrawide-field optical coherence tomography angiography (UWF-OCTA).

Methods

Observational, cross-sectional study evaluating ocular hemodynamics in patients with DR by SMI (Aplio i900, Canon Medical) and UWF-OCTA (BM-400 K BMizar, Tupai Medical Technology). The peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI) of the central retinal artery (CRA), posterior ciliary artery (PCA), and ophthalmic artery (OA) were measured by SMI. UWF-OCTA evaluated the fundus vascular parameters. A correlation analysis was used to determine the correlation between SMI and UWF-OCTA parameters.

Results

One hundred thirty-nine eyes of 139 diabetic patients were included: 29 without DR (NDR), 36 with mild to moderate nonproliferative DR (M-NPDR), 37 with severe NPDR (S-NPDR), and 37 with proliferative DR (PDR). PSV and EDV of retrobulbar vessels decreased from NDR to S-NPDR while increasing PDR. RI of OA showed a decreasing trend in the progression of DR, but other vessels didn’t show the same trend. ROC curve analysis showed that CRAPSV, CRAEDV, PCAEDV, OAPSV, and OAEDV had diagnostic value distinguishing M-NPDR and S-NPDR. The correlation analysis observed a significant association between the SMI parameters of CRA and PCA and UWF-OCTA parameters. CRA hemodynamics were more associated with fundus vascular parameters, especially the retina, in the NDR group than in the M-NPDR group. In contrast, PCA consistently correlated with fundus vascular parameters, especially in the choroid, from the NDR to the M-NPDR group. However, OA showed a poor correlation with OCTA parameters.

Conclusion

The velocity of retrobulbar vessels, mainly the CRA, may serve as a valuable predictor for assessing the progress of DR. The use of SMI in diabetic patients may help identify patients at risk of developing retinopathy.
“The targets…are driving the agenda and that probably needs to change”: stakeholder perspectives on HIV partner notification in sub-Saharan Africa
Authors: McGowan Maureen , Bärnighausen Kate , Berner-Rodoreda Astrid , McMahon Shannon A. , Mtaita Caroline , Mauti Joy , Neuhann Florian
Published: February 2024

Background

Voluntary assisted partner notification (VAPN) in HIV contact tracing is a globally recommended strategy to identify persons who have been exposed to HIV and link them to HIV testing and follow-up. However, there is little understanding about how VAPN is experienced by stakeholders in sub-Saharan African (SSA) contexts. We conducted a multi-level and multi-national qualitative analysis evaluating stakeholder perspectives surrounding VAPN implementation to inform the development of future VAPN policies.

Method

We conducted in-depth interviews (IDIs) with VAPN stakeholders at global (n = 5), national (n = 6), and community level (n = 4) across a total of seven SSA countries. Eligible participants were ≥ 18 years old and had experience developing, implementing, or overseeing VAPN policies in SSA. We sought to understand stakeholder’s perspectives on policy development, implementation, and perceived outcomes (barriers and facilitators). Interviews were audio recorded, transcribed, and analyzed thematically using a combination of inductive and deductive approaches.

Results

Between December 2019 and October 2020 we conducted 15 IDIs. While participants agreed that VAPN resulted in a high yield of people newly diagnosed with HIV; they noted numerous barriers surrounding VAPN implementation across global, national, and community levels, the majority of which were identified at community level. Barriers at global and national level included high target setting, contradictory laws, and limited independent research disenfranchising the experiences of implementing partners. The barriers identified at community level included client-level challenges (e.g., access to healthcare facilities and fear of adverse events); healthcare worker challenges (e.g., high workloads); limited data infrastructure; and cultural/gender norms that hindered women from engaging in HIV testing and VAPN services. In response to these barriers, participants shared implementation facilitators to sustain ethical implementation of VAPN services (e.g., contact tracing methods) and increase its yield (e.g., HIV self-testing integrated with VAPN services).

Conclusion

Overall, stakeholders perceived VAPN implementation to encounter barriers across all implementation levels (global to community). Future VAPN policies should be designed around the barriers and facilitators identified by SSA stakeholders to maximize the implementation of (ethical) HIV VAPN services and increase its impact in sub-Saharan African settings.
Analysis of the hikikomori phenomenon – an international infodemiology study of Twitter data in Portuguese
Authors: Correia Lopes Francisca , Pinto da Costa Mariana , Fernandez-Lazaro Cesar I , Lara-Abelenda Francisco J , Pereira-Sanchez Victor , Teo Alan R , Alvarez-Mon Miguel Angel
Published: February 2024

Background

Hikikomori refers to the extreme isolation of individuals in their own homes, lasting at least six months. In recent years social isolation has become an important clinical, social, and public health problem, with increased awareness of hikikomori around the globe. Portuguese is one of the six most spoken languages in the world, but no studies have analysed the content regarding this phenomenon expressed in Portuguese.

Objective

To explore the hikikomori phenomenon on Twitter in Portuguese, utilising a mixed-methods approach encompassing content analysis, emotional analysis, and correlation analysis.

Methods

A mixed methods analysis of all publicly available tweets in the Portuguese language using a specific keyword (hikikomori) between 1st January 2008 and 19th October 2022. The content analysis involved categorising tweets based on tone, content, and user types, while correlation analysis was used to investigate user engagement and geographical distribution. Statistical analysis and artificial intelligence were employed to classify and interpret the tweet data.

Results

Among the total of 13,915 tweets generated, in terms of tone 10,731 were classified as “negative”, and 3184 as “positive”. Regarding content, “curiosities” was the most posted, as well as the most retweeted and liked topic. Worldwide, most of the hikikomori related tweets in Portuguese were posted in Europe, while “individuals with hikikomori” were the users most active posting. Regarding emotion analysis, the majority of tweets were “neutral”.

Conclusions

These findings show the global prevalence of the discourse on hikikomori phenomenon among Portuguese speakers. It also indicates an increase in the number of tweets on this topic in certain continents over the years. These findings can contribute to developing specific interventions, support networks, and awareness-raising campaigns for affected individuals.
Systematic review and meta-analysis of single-stage vs two-stage revision for periprosthetic joint infection: a call for a prospective randomized trial
Authors: Zhao Yong , Fan Shaohua , Wang Zhangfu , Yan Xueli , Luo Hua
Published: February 2024

Background

Periprosthetic joint infection (PJI) is a severe complication of joint arthroplasty that causes significant pain and economic loss. This study aimed to determine whether the current evidence supports single-stage revision for PJI based on reinfection and reoperation rates.

Methods

We searched the PubMed, EBSCO, Medline, and Cochrane Library databases from inception to 30 May 2023 to identify studies that compared single-stage revision and two-stage revision for PJI. Data on reinfection and reoperation rates were pooled.

Results

This meta-analysis included a total of 40 studies with 8711 patients. Overall, there was no significant difference between single- and two-stage revision regarding the postoperative reinfection rate and reoperation rate. Subgroup analysis by surgery period and different surgical sites revealed no difference between the two groups in the reinfection and reoperation rates.

Conclusions

Based on the available evidence, our study did not identify a significant difference in reinfection and reoperation rates between single- and two-stage revision for PJI. Given the limitations in inclusion/exclusion criteria and the observed heterogeneity, we acknowledge the complexity of drawing strong conclusions. Therefore, we suggest that the choice between single- and two-stage revision should be carefully considered on an individual basis, taking into account patient-specific factors and further research developments.
Prospective learning curve analysis of en bloc resection of bladder tumor using an ex vivo porcine model
Authors: Yao Qiu , Jiang Huizhong , Niu Hui , Hu Guangmo , Liu Xiaolong , Xue Boxin
Published: February 2024

Background

As a relatively new surgical technique, the learning curve of en bloc resection of bladder tumor (ERBT) in ex vivo models remains unaddressed. This study aimed to explore the learning curve of ERBT in an ex vivo porcine model.

Methods

In this prospective study, eight endoscopists without prior experience in ERBT were divided into two groups: junior endoscopists, with less than 100 transurethral resection of bladder tumor (TURBT) procedure experience, and senior endoscopists, with at least 100 TURBT procedure experience. Each endoscopist performed 30 ERBT procedures on artificial lesions in an ex vivo porcine bladder model. The procedure time, perforation, en bloc resection status, and absence of detrusor muscle (DM) were recorded. The inflection points were identified using cumulative sum (CUSUM) analysis. Procedure results were compared between the two phases and two groups.

Results

In all, 240 artificial lesions were successfully resected using ERBT. The CUSUM regression line indicated the inflection point at the 16th procedure for the junior endoscopists and at the 13th procedure for the senior endoscopists. In both groups, the procedure time, perforation, piecemeal resection, and DM absence rates were significantly lower in the consolidation phase than in the initial phase. The procedure time for the senior endoscopists was lower than for the junior endoscopists in both phases.

Conclusions

ERBT performance improved significantly after reaching the inflection point of the learning curve in the ex vivo model. We recommend a minimum of 16 ERBT procedures in ex vivo models for urologists with less than 100 TURBT experience and a minimum of 13 procedures for those with at least 100 TURBT experience before advancing to live animal training or supervised clinical practice.
Comparison of Thulium Fiber Laser versus Holmium laser in ureteroscopic lithotripsy: a Meta-analysis and systematic review
Authors: Tang Xiaoyu , Wu Shaojie , Li Zhilong , Wang Du , Lei Cheng , Liu Tongzu , Wang Xinghuan , Li Sheng
Published: February 2024

Objectives

To compare the efficacy and safety of thulium fiber laser (TFL) to holmium: YAG (Ho: YAG) laser in ureteroscopic lithotripsy for urolithiasis.

Methods

PubMed, Web of Science, Embase, CENTRAL, SinoMed, CNKI database, VIP and Wanfang Database were systematically searched for all relevant clinical trials until September 2023. References were explored to identify the relevant articles. Meta-analysis was carried out for the retrieved studies using RevMan5.4.1 software, and the risk ratio, mean difference and 95% confidence interval were expressed. Statistical significance was set at p < 0.05. The main outcomes of this meta-analysis were stone-free rate (SFR), perioperative outcomes and intraoperative or postoperative complications.

Results

Thirteen studies, including 1394 patients, were included. According to the results of pooled analysis, TFL was associated with significantly higher stone-free rate (SFR) [0.52, 95% CI (0.32, 0.85), P = 0.009], shorter operation time [-5.47, 95% CI (-8.86, -2.08), P = 0.002], and less stone migration [0.17, 95% CI (0.06, 0.50), P = 0.001]. However, there was no significant difference in terms of the laser time, duration of hospital stay, drop of hemoglobin level, total energy, postoperative ureteral stenting, the incidence of intraoperative complications or postoperative complications between TFL and Ho: YAGs.

Conclusion

The findings of this study demonstrated several advantages of TFL in terms of higher SFR, shorter operative time and less stone migration.

Trial registration

The protocol of this systematic review was listed in PROSPERO (www.crd.york.ac.uk/PROSPERO) (Protocol number: CRD42022362550).
Application of deep learning and feature selection technique on external root resorption identification on CBCT images
Authors: Reduwan Nor Hidayah , Aziz Azwatee Abdul , Mohd Razi Roziana , Abdullah Erma Rahayu Mohd Faizal , Mazloom Nezhad Seyed Matin , Gohain Meghna , Ibrahim Norliza
Published: February 2024

Background

Artificial intelligence has been proven to improve the identification of various maxillofacial lesions. The aim of the current study is two-fold: to assess the performance of four deep learning models (DLM) in external root resorption (ERR) identification and to assess the effect of combining feature selection technique (FST) with DLM on their ability in ERR identification.

Methods

External root resorption was simulated on 88 extracted premolar teeth using tungsten bur in different depths (0.5 mm, 1 mm, and 2 mm). All teeth were scanned using a Cone beam CT (Carestream Dental, Atlanta, GA). Afterward, a training (70%), validation (10%), and test (20%) dataset were established. The performance of four DLMs including Random Forest (RF) + Visual Geometry Group 16 (VGG), RF + EfficienNetB4 (EFNET), Support Vector Machine (SVM) + VGG, and SVM + EFNET) and four hybrid models (DLM + FST: (i) FS + RF + VGG, (ii) FS + RF + EFNET, (iii) FS + SVM + VGG and (iv) FS + SVM + EFNET) was compared. Five performance parameters were assessed: classification accuracy, F1-score, precision, specificity, and error rate. FST algorithms (Boruta and Recursive Feature Selection) were combined with the DLMs to assess their performance.

Results

RF + VGG exhibited the highest performance in identifying ERR, followed by the other tested models. Similarly, FST combined with RF + VGG outperformed other models with classification accuracy, F1-score, precision, and specificity of 81.9%, weighted accuracy of 83%, and area under the curve (AUC) of 96%. Kruskal Wallis test revealed a significant difference (p = 0.008) in the prediction accuracy among the eight DLMs.

Conclusion

In general, all DLMs have similar performance on ERR identification. However, the performance can be improved by combining FST with DLMs.
Indigenizing and co-producing the ACGME anesthesiology milestone in Taiwan: a Delphi study and subgroup analysis
Authors: Kang Enoch Yi-No , Chi Kuan-Yu , Liao Faith , Liu Chih-Chung , Lin Chih-Peng , Chen Ta-Liang , Tanaka Pedro , Chen Chien-Yu
Published: February 2024

Background

To implement the ACGME Anesthesiology Milestone Project in a non-North American context, a process of indigenization is essential. In this study, we aim to explore the differences in perspective toward the anesthesiology competencies among residents and junior and senior visiting staff members and co-produce a preliminary framework for the following nation-wide survey in Taiwan.

Methods

The expert committee translation and Delphi technique were adopted to co-construct an indigenized draft of milestones. Descriptive analysis, chi-square testing, Pearson correlation testing, and repeated-measures analysis of variance in the general linear model were employed to calculate the F values and mean differences (MDs).

Results

The translation committee included three experts and the consensus panel recruited 37 participants from four hospitals in Taiwan: 9 residents, 13 junior visiting staff members (JVSs), and 15 senior visiting staff members (SVSs). The consensus on the content of the 285 milestones was achieved after 271 minor and 6 major modifications in 3 rounds of the Delphi survey. Moreover, JVSs were more concerned regarding patient care than were both residents (MD = − 0.095, P < 0.001) and SVSs (MD = 0.075, P < 0.001). Residents were more concerned regarding practice-based learning improvement than were JVSs (MD = 0.081; P < 0.01); they also acknowledged professionalism more than JVSs (MD = 0.072; P < 0.05) and SVSs (MD = 0.12; P < 0.01). Finally, SVSs graded interpersonal and communication skills lower than both residents (MD = 0.068; P < 0.05) and JVSs (MD = 0.065; P < 0.05) did.

Conclusions

Most ACGME anesthesiology milestones are applicable and feasible in Taiwan. Incorporating residents’ perspectives may bring insight and facilitate shared understanding to a new educational implementation. This study helped Taiwan generate a well-informed and indigenized draft of a competency-based framework for the following nation-wide Delphi survey.
Exploring the potential of ChatGPT as an adjunct for generating diagnosis based on chief complaint and cone beam CT radiologic findings
Authors: Hu Yanni , Hu Ziyang , Liu Wenjing , Gao Antian , Wen Shanhui , Liu Shu , Lin Zitong
Published: February 2024

Aim

This study aimed to assess the performance of OpenAI’s ChatGPT in generating diagnosis based on chief complaint and cone beam computed tomography (CBCT) radiologic findings.

Materials and methods

102 CBCT reports (48 with dental diseases (DD) and 54 with neoplastic/cystic diseases (N/CD)) were collected. ChatGPT was provided with chief complaint and CBCT radiologic findings. Diagnostic outputs from ChatGPT were scored based on five-point Likert scale. For diagnosis accuracy, the scoring was based on the accuracy of chief complaint related diagnosis and chief complaint unrelated diagnoses (1–5 points); for diagnosis completeness, the scoring was based on how many accurate diagnoses included in ChatGPT’s output for one case (1–5 points); for text quality, the scoring was based on how many text errors included in ChatGPT’s output for one case (1–5 points). For 54 N/CD cases, the consistence of the diagnosis generated by ChatGPT with pathological diagnosis was also calculated. The constitution of text errors in ChatGPT’s outputs was evaluated.

Results

After subjective ratings by expert reviewers on a five-point Likert scale, the final score of diagnosis accuracy, diagnosis completeness and text quality of ChatGPT was 3.7, 4.5 and 4.6 for the 102 cases. For diagnostic accuracy, it performed significantly better on N/CD (3.8/5) compared to DD (3.6/5). For 54 N/CD cases, 21(38.9%) cases have first diagnosis completely consistent with pathological diagnosis. No text errors were observed in 88.7% of all the 390 text items.

Conclusion

ChatGPT showed potential in generating radiographic diagnosis based on chief complaint and radiologic findings. However, the performance of ChatGPT varied with task complexity, necessitating professional oversight due to a certain error rate.
Comparison of immune checkpoint inhibitors related to pulmonary adverse events: a retrospective analysis of clinical studies and network meta-analysis
Authors: Hong Baohui , Du Bin , Chen Rong , Zheng Caiyun , Ni Ruping , Liu Maobai , Yang Jing
Published: February 2024

Background

Immune checkpoint inhibitors (ICIs) have transformed tumor treatment. However, the risk of pulmonary adverse events (PAEs) associated with ICI combination therapy is still unclear. We aimed to provide a PAE overview and risk ordering of ICIs used in tumor treatment.

Methods

We searched the databases of PubMed, PsycINFO, Embase, Cochrane Library, CINAHL, Web of Science, Scopus, and clinical trial websites during January 2011–April 2023 to identify phase II and III randomized clinical trials (RCTs) and single-arm clinical trials wherein at least one treatment arm received ICIs (e.g., ICI monotherapy, a combination of two ICIs, or ICIs in combination with conventional cancer therapy). We reported the results of PAEs. Additionally, we compared risks of PAEs between different drug classes using a Bayesian network meta-analysis.

Results

Among 143 RCTs and 24 single-arm trials, the incidence of all-grade and grade 3–4 PAEs were highest with programmed death L1 (PD-L1) plus cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and plus chemotherapy and anti-PD1 plus anti-CTLA4, the lowest with targeted therapy drug plus chemotherapy and anti-PD1 plus anti-PDL1. Anti-PD1 plus anti-CTLA4 and plus chemotherapy was the intervention with the highest risk for all-grade and 3–4 grade PAEs, and the intervention with the lowest risk was chemotherapy and anti-PD1 plus anti-PDL1. In terms of all-grade PAEs, chemotherapy was safer than ICI monotherapy. Except for the anti-PD1 plus anti-PDL1 regimen, no significant difference in the risk of grade 3–4 PAEs was detected between dual-ICIs and single-ICIs. Furthermore, the risk of PAEs associated with nivolumab, pembrolizumab, and atezolizumab may be dose dependent.

Conclusions

In the single-drug regimen, anti-PD1 caused the greatest incidence of PAEs. The risk of PAEs was higher with all single-ICIs than with chemotherapy. However, no significant difference in the risk of PAEs was detected between single-ICIs. In the combined regimen, anti-PD1 plus anti-CTLA4 and plus chemotherapy showed the greatest risk of PAEs, but there were no significant differences in risk between dual-ICIs and single-ICIs.
Genetic analysis of a pedigree with MECP2 duplication syndrome in China
Authors: Zeng Lan , Zhu Hui , Wang Jin , Wang Qiyan , Pang Ying , Luo Zemin , Chen Ai , Qin Shengfang , Zhu Shuyao
Published: February 2024

Background

MECP2 duplication syndrome (MDS) is a rare X-linked genomic disorder that primarily affects males. It is characterized by delayed or absent speech development, severe motor and cognitive impairment, and recurrent respiratory infections. MDS is caused by the duplication of a chromosomal region located on chromosome Xq28, which contains the methyl CpG binding protein-2 (MECP2) gene. MECP2 functions as a transcriptional repressor or activator, regulating genes associated with nervous system development. The objective of this study is to provide a clinical description of MDS, including imaging changes observed from the fetal period to the neonatal period.

Methods

Conventional G-banding was employed to analyze the chromosome karyotypes of all pedigrees under investigation. Subsequently, whole exome sequencing (WES), advanced biological information analysis, and pedigree validation were conducted, which were further confirmed by copy number variation sequencing (CNV-seq).

Results

Chromosome karyotype analysis revealed that a male patient had a chromosome karyotype of 46,Y,dup(X)(q27.2q28). Whole-exon duplication in the MECP2 gene was revealed through WES results. CNV-seq validation confirmed the presence of Xq27.1q28 duplicates spanning 14.45 Mb, which was inherited from a mild phenotype mother. Neither the father nor the mother's younger brother carried this duplication.

Conclusion

In this study, we examined a male child in a family who exhibited developmental delay and recurrent respiratory tract infections as the main symptoms. We conducted thorough family investigations and genetic testing to determine the underlying causes of the disease. Our findings will aid in early diagnosis, genetic counseling for male patients in this family, as well as providing prenatal diagnosis and reproductive guidance for female carriers.
The oncolytic bacteria-mediated delivery system of CCDC25 nucleic acid drug inhibits neutrophil extracellular traps induced tumor metastasis
Authors: Liu Li-na , Chen Chen , Xin Wen-jie , Li Qiang , Han Chao , Hua Zi-chun
Published: February 2024

Background

Neutrophil extracellular traps (NETs), antibacterial weapons of neutrophils (NEs), have been found to play a crucial role in cancer metastasis in recent years. More and more cancer research is focusing on anti-NETs. However, almost all anti-NETs treatments have limitations such as large side effects and limited efficacy. Therefore, exploring new anti-NETs therapeutic strategies is a long-term goal.

Results

The transmembrane protein coiled-coil domain containing 25 (CCDC25) on tumor cell membranes can bind NETs-DNA with high specificity and affinity, enabling tumor cells to sense NETs and thus promote distant metastasis. We transformed shCCDC25 into VNP20009 (VNP), an oncolytic bacterium, to generate VNP-shCCDC25 and performed preclinical evaluation of the inhibitory effect of shCCDC25 on cancer metastasis in B16F10 lung metastasis and 4T1 orthotopic lung metastasis models. VNP-shCCDC25 effectively blocked the downstream prometastatic signaling pathway of CCDC25 at tumor sites and reduced the formation of NETs while recruiting more neutrophils and macrophages to the tumor core, ultimately leading to excellent metastasis inhibition in the two lung metastasis models.

Conclusion

This study is a pioneer in focusing on the effect of anti-NET treatment on CCDC25. shCCDC25 is effectively delivered to tumor sites via the help of oncolytic bacteria and has broad application in the inhibition of cancer metastasis via anti-NETs.

Graphical Abstract
M2 macrophage-derived exosomal miR-26b-5p regulates macrophage polarization and chondrocyte hypertrophy by targeting TLR3 and COL10A1 to alleviate osteoarthritis
Authors: Qian Yufan , Chu Genglei , Zhang Lei , Wu Zhikai , Wang Qiuyuan , Guo Jiong Jiong , Zhou Feng
Published: February 2024

Osteoarthritis (OA) is one of the most prevalent chronic musculoskeletal diseases among the elderly population. In this study, macrophage-derived exosomes were isolated and identified. Exosomes were subjected to microRNA (miRNA) sequencing and bioinformatic analysis, and differentially expressed miRNAs were verified. miR-26b-5p target genes were confirmed through target-site mutation combined with a dual-luciferase reporter assay. The effects of miR-26b-5p on macrophage polarization and chondrocyte hypertrophy were assessed in vitro. miR-26b-5p agomir was applied to mice with OA induced by anterior cruciate ligament transection (ACLT). The therapeutic effects of miR-26b-5p were evaluated via pain behavior experiments and histological observations. In vitro, miR-26b-5p repolarized M1 macrophages to an anti-inflammatory M2 type by targeting the TLR3 signaling pathway. miR-26b-5p could target COL10A1, further inhibiting chondrocyte hypertrophy induced by M1 macrophage-conditioned medium (M1-CM). In vivo, miR-26b-5p agomir ameliorated gait abnormalities and mechanical allodynia in OA mice. miR-26b-5p treatment attenuated synovitis and cartilage degeneration, thereby delaying OA progression. In conclusion, M2 macrophage-derived exosomal miR-26b-5p could protect articular cartilage and ameliorate gait abnormalities in OA mice by targeting TLR3 and COL10A1. miR-26b-5p further affected macrophage polarization and chondrocyte hypertrophy. Thus, this exosomal miR-26b-5p-based strategy might be a potential method for OA treatment.

Graphical Abstract
Link between organic nanovescicles from vegetable kingdom and human cell physiology: intracellular calcium signalling
Authors: Trentini Martina , Zanolla Ilaria , Tiengo Elena , Zanotti Federica , Sommella Eduardo , Merciai Fabrizio , Campiglia Pietro , Licastro Danilo , Degasperi Margherita , Lovatti Luca , Bonora Massimo , Danese Alberto , Pinton Paolo , Zavan Barbara
Published: February 2024

Background

Plant-derived nanovesicles (PDNVs) are a novelty in medical and agrifood environments, with several studies exploring their functions and potential applications. Among fruits, apples (sp. Malus domestica) have great potential as PDNVs source, given their widespread consumption, substantial waste production, and recognized health benefits. Notably, apple-derived nanovesicles (ADNVs) can interact with human cell lines, triggering anti-inflammatory and antioxidant responses. This work is dedicated to the comprehensive biochemical characterization of apple-derived nanovesicles (ADNVs) through proteomic and lipidomic analysis, and small RNAs sequencing. This research also aims to shed light on the underlying mechanism of action (MOA) when ADNVs interface with human cells, through observation of intracellular calcium signalling in human fibroblasts, and to tackles differences in ADNVs content when isolated from fruits derived from integrated and organic production methods cultivars.

Results

The ADNVs fraction is mainly composed of exocyst-positive organelles (EXPOs) and MVB-derived exosomes, identified through size and molecular markers (Exo70 and TET-3-like proteins). ADNVs’ protein cargo is heterogeneous and exhibits a diverse array of functions, especially in plant's protection (favouring ABA stress-induced signalling, pathogen resistance and Reactive Oxygen Species (ROS) metabolism). Noteworthy plant miRNAs also contribute to phytoprotection. In relation with human cells lines, ADNVs elicit spikes of intracellular Ca2+ levels, utilizing the cation as second messenger, and produce an antioxidant effect. Lastly, organic samples yield a substantial increase in ADNV production and are particularly enriched in bioactive lysophospholipids.

Conclusions

We have conclusively demonstrated that ADNVs confer an antioxidant effect upon human cells, through the initiation of a molecular pathway triggered by Ca2+ signalling. Within ADNVs, a plethora of bioactive proteins, small RNAs, and lipids have been identified, each possessing well-established functions within the realm of plant biology. While ADNVs predominantly function in plants, to safeguard against pathogenic agents and abiotic stressors, it is noteworthy that proteins with antioxidant power might act as antioxidants within human cells.

Graphical Abstract
NIR-IIb fluorescence antiangiogenesis copper nano-reaper for enhanced synergistic cancer therapy
Authors: Li Wenling , Xin Huan , Gao Wenjuan , Yuan Pengjun , Ni Feixue , Ma Jingyi , Sun Jingrui , Xiao Jianmin , Tian Geng , Liu Lu , Zhang Guilong
Published: February 2024

The formation of blood vessel system under a relatively higher Cu2+ ion level is an indispensable precondition for tumor proliferation and migration, which was assisted in forming the tumor immune microenvironment. Herein, a copper ions nano-reaper (LMDFP) is rationally designed not only for chelating copper ions in tumors, but also for combination with photothermal therapy (PTT) to improve antitumor efficiency. Under 808 nm laser irradiation, the fabricated nano-reaper converts light energy into thermal energy to kill tumor cells and promotes the release of D-penicillamine (DPA) in LMDFP. Photothermal properties of LMDFP can cause tumor ablation in situ, which further induces immunogenic cell death (ICD) to promote systematic antitumor immunity. The released DPA exerts an anti-angiogenesis effect on the tumor through chelating copper ions, and inhibits the expression of programmed death ligand 1 (PD-L1), which synergizes with PTT to enhance antitumor immunity and inhibit tumor metastasis. Meanwhile, the nanoplatform can emit near-infrared-IIb (NIR-IIb) fluorescence under 980 nm excitation, which can be used to track the nano-reaper and determine the optimal time point for PTT. Thus, the fabricated nano-reaper shows powerful potential in inhibiting tumor growth and metastasis, and holds great promise for the application of copper nanochelator in precise tumor treatment.
C-Myc protein expression indicates unfavorable clinical outcome in surgically resected small cell lung cancer
Authors: Lang Christian , Megyesfalvi Zsolt , Lantos Andras , Oberndorfer Felicitas , Hoda Mir Alireza , Solta Anna , Ferencz Bence , Fillinger Janos , Solyom-Tisza Anna , Querner Alessandro Saeed , Egger Felix , Boettiger Kristiina , Klikovits Thomas , Timelthaler Gerald , Renyi-Vamos Ferenc , Aigner Clemens , Hoetzenecker Konrad , Laszlo Viktoria , Schelch Karin , Dome Balazs
Published: February 2024

Background

By being highly involved in the tumor evolution and disease progression of small cell lung cancer (SCLC), Myc family members (C-Myc, L-Myc, and N-Myc) might represent promising targetable molecules. Our aim was to investigate the expression pattern and prognostic relevance of these oncogenic proteins in an international cohort of surgically resected SCLC tumors.

Methods

Clinicopathological data and surgically resected tissue specimens from 104 SCLC patients were collected from two collaborating European institutes. Tissue sections were stained by immunohistochemistry (IHC) for all three Myc family members and the recently introduced SCLC molecular subtype-markers (ASCL1, NEUROD1, POU2F3, and YAP1).

Results

IHC analysis showed C-Myc, L-Myc, and N-Myc positivity in 48%, 63%, and 9% of the specimens, respectively. N-Myc positivity significantly correlated with the POU2F3-defined molecular subtype (r = 0.6913, p = 0.0056). SCLC patients with C-Myc positive tumors exhibited significantly worse overall survival (OS) (20 vs. 44 months compared to those with C-Myc negative tumors, p = 0.0176). Ultimately, in a multivariate risk model adjusted for clinicopathological and treatment confounders, positive C-Myc expression was confirmed as an independent prognosticator of impaired OS (HR 1.811, CI 95% 1.054–3.113, p = 0.032).

Conclusions

Our study provides insights into the clinical aspects of Myc family members in surgically resected SCLC tumors. Notably, besides showing that positivity of Myc family members varies across the patients, we also reveal that C-Myc protein expression independently correlates with worse survival outcomes. Further studies are warranted to investigate the role of Myc family members as potential prognostic and predictive markers in this hard-to-treat disease.
Molting incidents of Hyalomma spp. carrying human pathogens in Germany under different weather conditions
Authors: Chitimia-Dobler Lidia , Springer Andrea , Lang Daniel , Lindau Alexander , Fachet Katrin , Dobler Gerhard , Nijhof Ard M. , Strube Christina , Mackenstedt Ute
Published: February 2024

Background

Hyalomma marginatum and H. rufipes are two-host tick species, which are mainly distributed in southern Europe, Africa to central Asia but may also be found in Central and Northern Europe through introduction by migratory birds.

Methods

Ticks were collected while feeding or crawling on animals and humans, or from the environment, in different regions in Germany, between 2019 and 2021 in a citizen science study and from 2022 to 2023 in the wake of this study.

Results

From 2019 to 2023, a total of 212 Hyalomma adult ticks were detected in Germany. This included 132 H. marginatum and 43 H. rufipes ticks sent to research institutions and 37 photographic records that were only identified to genus level. The number of detected ticks varied over the years, with the highest number of 119 specimens recorded in 2019, followed by 57 in 2020. Most of the specimens were collected from horses, while some were collected from other animals, humans or found crawling on human clothes or other objects inside or outside houses. The screening of 175 specimens for Crimean-Congo hemorrhagic fever virus and of 132 specimens for Babesia/Theileria spp. by PCR gave negative results, while human-pathogenic Rickettsia were detected in 44% (77/175) of the total samples. Subsequent amplicon sequencing and phylogenetic analysis of representative samples determined the species of 41 Rickettsia aeschlimannii and one R. slovaca sequences.

Conclusions

Analysis of climatic factors indicated a significantly higher probability of Hyalomma occurrence at locations with higher average spring temperature during the years 2019 and 2020 compared to randomly generated pseudo-absence locations. Dry and hot conditions probably facilitated Hyalomma nymphs’ survival and molting into adults during these years.

Graphical Abstract
Intra-prostatic tumour evolution, steps in metastatic spread and histogenomic associations revealed by integration of multi-region whole-genome sequencing with histopathological features
Authors: Rao Srinivasa , Verrill Clare , Cerundolo Lucia , Alham Nasullah Khalid , Kaya Zeynep , O’Hanlon Miriam , Hayes Alicia , Lambert Adam , James Martha , Tullis Iain D. C. , Niederer Jane , Lovell Shelagh , Omer Altan , Lopez Francisco , Leslie Tom , Buffa Francesca , Bryant Richard J. , Lamb Alastair D. , Vojnovic Boris , Wedge David C. , Mills Ian G. , Woodcock Dan J. , Tomlinson Ian , Hamdy Freddie C.
Published: February 2024

Background

Extension of prostate cancer beyond the primary site by local invasion or nodal metastasis is associated with poor prognosis. Despite significant research on tumour evolution in prostate cancer metastasis, the emergence and evolution of cancer clones at this early stage of expansion and spread are poorly understood. We aimed to delineate the routes of evolution and cancer spread within the prostate and to seminal vesicles and lymph nodes, linking these to histological features that are used in diagnostic risk stratification.

Methods

We performed whole-genome sequencing on 42 prostate cancer samples from the prostate, seminal vesicles and lymph nodes of five treatment-naive patients with locally advanced disease. We spatially mapped the clonal composition of cancer across the prostate and the routes of spread of cancer cells within the prostate and to seminal vesicles and lymph nodes in each individual by analysing a total of > 19,000 copy number corrected single nucleotide variants.

Results

In each patient, we identified sample locations corresponding to the earliest part of the malignancy. In patient 10, we mapped the spread of cancer from the apex of the prostate to the seminal vesicles and identified specific genomic changes associated with the transformation of adenocarcinoma to amphicrine morphology during this spread. Furthermore, we show that the lymph node metastases in this patient arose from specific cancer clones found at the base of the prostate and the seminal vesicles. In patient 15, we observed increased mutational burden, altered mutational signatures and histological changes associated with whole genome duplication. In all patients in whom histological heterogeneity was observed (4/5), we found that the distinct morphologies were located on separate branches of their respective evolutionary trees.

Conclusions

Our results link histological transformation with specific genomic alterations and phylogenetic branching. These findings have implications for diagnosis and risk stratification, in addition to providing a rationale for further studies to characterise the genetic changes causally linked to morphological transformation. Our study demonstrates the value of integrating multi-region sequencing with histopathological data to understand tumour evolution and identify mechanisms of prostate cancer spread.
Recent advances in polygenic scores: translation, equitability, methods and FAIR tools
Authors: Xiang Ruidong , Kelemen Martin , Xu Yu , Harris Laura W. , Parkinson Helen , Inouye Michael , Lambert Samuel A.
Published: February 2024

Polygenic scores (PGS) can be used for risk stratification by quantifying individuals’ genetic predisposition to disease, and many potentially clinically useful applications have been proposed. Here, we review the latest potential benefits of PGS in the clinic and challenges to implementation. PGS could augment risk stratification through combined use with traditional risk factors (demographics, disease-specific risk factors, family history, etc.), to support diagnostic pathways, to predict groups with therapeutic benefits, and to increase the efficiency of clinical trials. However, there exist challenges to maximizing the clinical utility of PGS, including FAIR (Findable, Accessible, Interoperable, and Reusable) use and standardized sharing of the genomic data needed to develop and recalculate PGS, the equitable performance of PGS across populations and ancestries, the generation of robust and reproducible PGS calculations, and the responsible communication and interpretation of results. We outline how these challenges may be overcome analytically and with more diverse data as well as highlight sustained community efforts to achieve equitable, impactful, and responsible use of PGS in healthcare.
Public health spending in Sub-Saharan Africa: exploring transmission mechanisms using the latent growth curve mediation model
Authors: Kabongo Wa Ntita Serge , Mbonigaba Josue
Published: February 2024

In response to the imperatives of universal health coverage, structural factors that may hinder the effectiveness of increased spending in sub-Saharan Africa (SSA) need attention. This study assessed the mediating role of these factors in domestic general government health expenditure (DGGHE) effects to propose solutions for improving population health outcomes (PHO). The analysis used the Latent Growth Curve Mediation Model (LGCMM) approach within the structural equation model (SEM) framework for panel data from 42 SSA countries from 2015 to 2018. The findings were that malaria and female education formed a channel through which DGGHE imparted its effects on DALY in SSA, and these effects were achieved via the specific path from the DGGHE slope to the DALY slope, via malaria and female education slopes. However, the paper found no evidence of immunization coverage mediating the relationship between DGGHE and DALY in SSA. The paper concludes that structural factors affect the effectiveness of DGGHE on PHO, implying that governments should emphasize existing programs to fight against malaria and increase immunization coverage.