bluuebunny/crossref_metadata_2025 huggingface dataset:
Rate of decline in kidney function with age: a systematic review
Authors: Guppy Michelle , Thomas Elizabeth Taruna , Glasziou Paul , Clark Justin , Jones Mark , O'Hara Daniel Vincent , Doust Jenny
Published: November 2024

Objective

To determine the distribution of kidney function values as measured by glomerular filtration rate (GFR), and the rate of decline with age in male and female healthy subjects without pre-existing medical conditions.

Design

Systematic review and structured synthesis.

Search sources

PubMed, Embase, Cochrane Central Register of Controlled Trials and Web of Science, from database inception to 25 October 2023. Unpublished studies were searched from clinical trial registries and the grey literature.

Selection criteria

Observational cohort studies, including non-treatment arms of randomised, pseudorandomised and non-randomised controlled trials that assessed the age-related decline in kidney function over time.

Main outcome measures

Primary outcomes were rate of change of kidney function over time (absolute and relative change) and rate of change of kidney function with age. Secondary outcomes included rate of change of kidney function compared with baseline GFR, gender, ethnicity and proportion of participants >60 years defined as having chronic kidney disease.

Data collection and analysis

Two review authors independently screened studies for inclusion, extracted data and assessed risk of bias. Data could not be pooled because of significant heterogeneity. Instead, a descriptive analysis was used to synthesise results.

Results

12 studies between 1958 and 2021 reported the decline rate of kidney function in healthy individuals: six prospective cohort studies, four retrospective cohort studies and two randomised controlled clinical trials, which included 129 359 healthy participants (range from 15 to 46 682) and ranged from 2 to 23 years duration. Annual decline rates ranged from −0.24 to −3.60 mL/min/1.73 m2/year (−0.37 to −1.07 in subjects without hypertension). Results were mixed as to whether decline rates sped up or slowed down with age, and whether decline rates differed between women and men, with studies showing conflicting results. This study was unable to determine the decline rates in different ethnicities.

Conclusions

This study is the first systematic review to investigate the longitudinal decline in kidney function with age in healthy individuals. The normal decline rate could be considered between −0.37 and −1.07 mL/min/1.73 m2/year in healthy adults without hypertension. Kidney function decline rates in healthy adults may be helpful to clinicians anticipating patients’ kidney trajectory and determining whether chronic kidney disease-specific care is required.

PROSPERO registration number

CRD42023096888.
Evaluation of safety and efficacy of intracranial self-expanding drug-eluting stents for symptomatic intracranial atherosclerotic stenosis: a prospective, multicentre, randomised controlled, superiority clinical trial protocol
Authors: Zhu Zhengpeng , He Yanyan , Zhao Jingge , Liu Wenbo , Ding Qianhao , Li Shikai , Pang Yukuan , Zhao Yang , Zhu Liangfu , Wang Ziliang , Li Tianxiao , He Yingkun
Published: November 2024

Background

In-stent restenosis (ISR) is a crucial factor that affects the long-term efficacy of intracranial bare metal stent (BMS) implantation for intracranial atherosclerotic stenosis (ICAS). Patients with intracranial ISR are at a high risk of recurrent ischaemic events. The NOVA intracranial drug-eluting stent (DES) trial demonstrates that a DES can reduce ISR and stroke recurrence after intracranial bare stent implantation. However, the application of balloon-expanded DES necessitates specific vascular conditions. The objective of this study is to assess the safety and efficacy of self-expanding DES for treating symptomatic ICAS (sICAS).

Methods

This is a prospective, multicentre, randomised, controlled, superiority clinical trial that is conducted in 16 clinical trial centres in China. This study aims to recruit 208 patients with sICAS. Eligible subjects are randomly assigned to two groups at a ratio of 1:1. The experimental group is treated with DES (Xinwei intracranial DES system). The control group is treated with BMS (Wingspan intracranial stent system). All subjects are followed up within 7 days after surgery or before discharge; 30 days after surgery; and 6, 12 and 24 months after surgery. The primary outcome of the trial is the incidence of ISR at 6 months after surgery to verify the safety and efficacy of intracranial DESs. After 6 months of follow-up, the clinical summary report is issued for product registration application, and the follow-up of 12 months and 24 months after operation is conducted to evaluate the medium and long-term efficacy.

Ethics and dissemination

The study involving human participants is reviewed and approved by the Ethics Committee of Drugs (devices) Clinical Experiment in Henan Provincial People’s Hospital (reference number: AF/SC-08/05.0) and other research centres participating in the clinical trial (supplemental file 2). The results yield from this study will be presented at international conferences and sent to a peer-reviewed journal to be considered for publication.

Trial registration number

Registered on 2 November 2023 with Chinese clinical trial registry. Registration number is ChiCTR2300077271.
Knowledge, attitude and practice of urticaria patients towards urticaria medication treatment: a cross-sectional study at the first affiliated hospital of Kunming Medical University
Authors: Shen Yan , Zhao Weijia
Published: November 2024

Objectives

To explore the knowledge, attitudes and practices (KAP) of urticaria patients regarding the medication treatment.

Methods design

A cross-sectional study.

Setting

At the Dermatology Department of the First Affiliated Hospital of Kunming Medical University from 15 June 2023 to 12 March 2024.

Participants

Urticaria patients.

Primary and secondary outcome measures

The primary outcome was KAP of urticaria patients using a self-administered questionnaire. The secondary outcomes were factors associated with KAP.

Results

A total of 497 valid responses were collected. Of these respondents, 333 (67.0%) were female, and 375 (75.5%) lived in urban areas. The median KAP scores were 1.00 [0.00, 3.00] (possible range: 0–8), 23.00 [18.00, 26.00] (possible range: 10–50) and 32.00 [31.00, 36.00] (possible range: 8–40), respectively. Most patients (91.7%) clearly needed to understand the aetiology and treatment process related to urticaria. Less than half (43.5%) of patients believed that their healthcare providers offered comprehensive information about the knowledge and procedures related to urticaria medication. Demographic analysis uncovered substantial variations in knowledge and attitude scores across different education levels, age groups, occupations and residential areas (p<0.001 for all). In contrast, the impact on practice scores was less significant, particularly concerning educational diversity. Multivariate logistic regression analysis revealed that a higher knowledge score (OR=1.17, 95% CI: [1.03 to 1.33], p=0.014) and age between 35–65 years (OR=1.78, 95% CI: [1.16 to 2.74], p=0.009) were independently associated with proactive practices.

Conclusion

Urticaria patients exhibit insufficient knowledge, unfavourable attitudes and proactive practices concerning medication treatment. Enhancing patient education and targeted interventions are essential to improve the knowledge and attitudes towards medication treatment, ultimately promoting better self-management practices among urticaria patients.
Effect of desflurane, sevoflurane or propofol on the incidence of postoperative delirium in older adults undergoing moderate- to high-risk major non-cardiac surgery: study protocol for a prospective, randomised, observer-blinded, clinical trial (RAPID-II trial)
Authors: Taschner Alexander , Fleischmann Edith , Kabon Barbara , Sinner Barbara , Eckhardt Christine , Horvath Katharina , Adamowitsch Nikolas , Hantakova Nicole , Hochreiter Beatrix , Zotti Oliver , Fraunschiel Melanie , Graf Alexandra , Reiterer Christian
Published: November 2024

Introduction

The effect of different anaesthetics on the incidence of postoperative delirium is still not entirely clear. Therefore, we will evaluate the effect of desflurane versus sevoflurane versus propofol for the maintenance of anaesthesia on the incidence of postoperative delirium in older adults undergoing moderate- to high-risk major non-cardiac surgery. We will further compare the incidences of delayed neurocognitive recovery, long-term postoperative neurocognitive disorder, postoperative nausea and vomiting between the groups.

Methods and analysis

In this multicentre, prospective, observer-blinded, randomised controlled clinical trial, we will include 1332 patients ≥65 years of age undergoing moderate- to high-risk major non-cardiac surgery lasting at least 2 hours. Patients will be randomly 1:1:1 assigned to receive desflurane, sevoflurane or propofol for anaesthesia. Maintenance of anaesthesia will be performed in a goal-directed manner using processed electroencephalography with an intraoperative goal of bispectral index 40–60. Our primary outcome will be the incidence of postoperative delirium within the first five postoperative days. Postoperative delirium will be assessed using the three-dimensional-confusion assessment method (3D-CAM) or CAM-intensive care unit (ICU) in the morning and evening of the first five postoperative days by blinded study personnel. The primary outcome, the incidence of postoperative delirium, will be compared between the three study groups using a χ2test. Furthermore, a logistic regression model for the incidence of postoperative delirium will be performed, accounting for randomised groups as well as other predefined confounding factors.

Ethics and dissemination

This clinical trial has been approved by the ethics committee and the Federal Office for Safety in Healthcare as the competent authority for clinical trials in Austria. The results of this trial will be published in a peer-reviewed journal.

Trial registration number

ClinicalTrials.govNCT05990790.
Implementation strategies for providing optimised tuberculosis and diabetes integrated care in LMICs (POTENTIAL): protocol for a multiphase sequential and concurrent mixed-methods study
Authors: Afaq Saima , Zala Zala , Aleem Saima , Qazi Fatima Khalid , Jamal Syeda Fatima , Khan Zohaib , Sarfraz Mariyam , Niazi Asima Khan , Safdar Nauman , Basit Abdul , Ul-Haq Zia , Iqbal Romaina , Fatima Razia , Hewitt Catherine , Siddiqi Najma , Parrott Steve , Siddiqi Kamran
Published: November 2024

Introduction

Almost a quarter of patients with tuberculosis (TB) in Pakistan may also have diabetes, with an additional quarter in a pre-diabetic state. Diabetes is a risk factor for TB. When it co-occurs with TB, it leads to poorer outcomes for both conditions, considerably increasing the burden on individuals, families and the healthcare system. We aim to improve health, quality of life and economic outcomes for people with TB and diabetes by optimising diabetes prevention, screening and management within TB care. The objectives of this study are to: (1) design an integrated optimised tuberculosis-diabetes care package (Opt-TBD) and its implementation strategies; (2) pilot and refine these implementation strategies and (3) implement and evaluate the Opt-TBD care package in 15 TB care facilities in Pakistan.

Methods and analysis

We will work with the TB programme across two provinces of Pakistan: Khyber Pakhtunkhwa and Punjab. TB care facilities will be selected from urban and rural settings of these provinces and will include three levels: primary, secondary and tertiary care settings. This multiphase mixed-method study has three sequential phases. Once ready, the care package and its implementation strategies will be piloted to inform further refinement. The package will be implemented in 15 urban and rural TB care facilities and evaluated for its Reach, Effectiveness, Adoption, Implementation and Maintenance, and potential for scale-up. Quantitative data will assess provider adoption and the package’s accessibility and effectiveness for patients with TB and with diabetes and pre-diabetes. Qualitative data will explore barriers and facilitators for successful implementation and scale-up. Data will be analysed using statistical methods—including descriptive and inferential statistics—for quantitative data and framework analysis for qualitative data, with triangulation to integrate findings.

Ethics and dissemination

Ethics approval was granted by the National Bioethics Committee of Pakistan (NBCR-1010). Findings will be shared through academic publications, conferences and public outreach.
Quality improvement initiative: use of the STOP-BANG score and monitoring to reduce adverse events in hospitalised patients at risk of obstructive sleep apnoea
Authors: Lauer Kathryn K , Zhang Donglin , Lunar Lauren , Landry Curtis , Welter Jennifer , Flemming Kellianne , Franco Rose , Siclovan Danielle , Avdeev Jamie , Woodson B Tucker , Szabo Aniko , Truwit Jonathon D , Hainsworth Keri R
Published: November 2024

Background

Obstructive sleep apnoea increases risk of respiratory depression with administration of sedatives, narcotics or anxiolytics. To reduce adverse events during hospital admission, we implemented STOP-BANG screening to prompt respiratory monitoring for inpatients receiving these medications. This study reports on protocol development, implementation and an initial analysis over 5 years to evaluate implementation success and outcomes.

Intervention

The STOP-BANG measure was embedded in the nurse navigator at admission. If the score was ≥3 and sedatives, narcotics and/or anxiolytics were ordered, the provider was prompted to monitor patients with continuous pulse oximetry and/or capnography.

Methods

We assessed the impact of the intervention using a retrospective pre–post design. Preprotocol data from all adult inpatients over a 2.5-year period, and postprotocol data from all adult inpatients from over a 5-year period, were extracted from the electronic health record. Outcomes included use of monitoring; adverse events during hospitalisation were included to evaluate the effects of the intervention: mortality, rate of rapid response team events, reversal and/or rescue, intensive care unit admission and orders for positive airway pressure equipment.

Results

The combined preprotocol and postprotocol sample included 254 121 patients. After protocol implementation, overall mortality for patients receiving sedatives, narcotics or anxiolytics decreased slightly from 2.1% to 1.9% (p<0.001). In the postprotocol cohort only (n=193 744), monitored patients had a higher probability of experiencing all adverse events. Among monitored patients, mortality was lowest in the high-risk group (STOP-BANG≥5).

Discussion

Triaging by STOP-BANG coupled with monitoring appeared to be helpful for patients at highest risk of obstructive sleep apnoea. Given the complexity of obstructive sleep apnoea, further pursuit of subphenotypes is warranted.
Implementing and validating newborn screening for inborn errors of metabolism in South India: a 2-year observational study at a tertiary care hospital
Authors: Chikkalingaiah Manju Hosuru , Bevinakoppamath Supriya , Archana Surajj S , Kapa Aishwarya , Kempegowda Swetha N , Shivashankar Kusuma K , Ramachandra Shobha C , K Basavarajaiah Suma , Nataraj Suma , Prashant Akila
Published: November 2024

Introduction

Newborn screening (NBS) is an essential public health initiative for early diagnosis of inborn errors of metabolism (IEM), where timely intervention can reduce morbidity and mortality. While routine in developed countries, NBS is not widely practised in India. This study aimed to implement NBS programme in a tertiary care hospital in South India and validate predetermined cut-off values tailored to the regional population.

Methods

Between 2020 and 2022, 5157 neonates were screened for congenital hypothyroidism (CH), congenital adrenal hyperplasia (CAH), cystic fibrosis (CF), glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDD), phenylketonuria (PKU), galactosemia and biotinidase deficiency. Screening was performed using dissociation-enhanced lanthanide fluorescent immunoassay technology on Victor2D platform (Revvity). Markers assessed included 17-α-OH progesterone, neonatal thyroid stimulating hormone, total galactose, immunoreactive trypsinogen, G6PD enzyme, biotinidase enzyme and phenylalanine levels. Data analysis was conducted using R V.4.1.1 software.

Results

Of the 5157 neonates, the recall rates were consistent with those reported in similar studies. However, only 26.7% of screen-positive newborns returned for retesting, indicating a significant gap in awareness about IEMs and the importance of follow-up. Of these, none were diagnosed with CAH; however, four were found to have CH, two had galactosemia, three had G6PDD, one had CF, one had PKU and none had biotinidase deficiency. The confirmed cases were promptly treated and monitored regularly. The distribution of each marker’s values fell within 2.5th–97.5th percentiles suggesting consistency.

Conclusion

The reference ranges provided by the manufacturer appear valid in the Indian context. A key challenge identified was low follow-up compliance for screen-positive infants, highlighting the need for enhanced public education on IEM and NBS. Future research will focus on determining the incidence of IEMs and improving parental awareness and follow-up rates.
Differences in dementia prevention knowledge by educational attainment: an analysis of a household survey from Great Britain
Authors: Nafilyan Vahe , Eley Sarah , Courtin Emilie
Published: November 2024

Background

Higher levels of education are associated with slower cognitive decline and a lower risk of dementia, with some evidence of a causal relationship. However, the mechanisms explaining these associations are not well established.

Methods

We collected data on dementia knowledge using a cross-sectional household survey representative of the population of Great Britain. Dementia knowledge was assessed using a self-reported measure and a question measuring the knowledge of key risk factors. We examined whether dementia knowledge varied by levels of education (as measured by the level of the highest qualification) by fitting logistic regressions adjusted for confounding factors.

Findings

Out of the 5036 respondents aged 25 or over (46.6% male; average age 63.8), 9.3% reported knowing a great deal about dementia, and 32.2% quite a lot. We found a strong educational gradient in dementia prevention knowledge. For people with a degree qualification compared with people with no formal qualification, the ORs of reporting having quite a lot or a great deal of knowledge about dementia were 2.54 (95% CIs 1.81 to 3.56). The ORs were 3.58 (2.61 to 4.91) for mentioning all risk factors. The difference in awareness by educational level was largest for some risk factors such as lack of physical and mental activity, alcohol consumption and poor mental health.

Interpretation

The protective effect of higher levels of education against the risk of dementia may partly be driven by differences in dementia prevention knowledge. Health education efforts on dementia prevention should target people with lower levels of education to reduce inequalities in dementia prevalence.
Camrelizumab plus carboplatin and pemetrexed as first-line therapy for advanced non-squamous non-small-cell lung cancer: 5-year outcomes of the CameL randomized phase 3 study
Authors: Zhou Caicun , Chen Gongyan , Huang Yunchao , Zhou Jianying , Lin LiZhu , Feng Jifeng , Wang Zhehai , Shu Yongqian , Shi Jianhua , Hu Yi , Wang QiMing , Cheng Ying , Wu Fengying , Chen Jianhua , Lin Xiaoyan , Wang Yongsheng , Huang Jianan , Cui Jiuwei , Cao Lejie , Liu Yunpeng , Zhang Yiping , Pan Yueyin , Zhao Jun , Wang LiPing , Chang Jianhua , Chen Qun , Ren Xiubao , Zhang Wei , Fan Yun , He Zhiyong , Fang Jian , Gu Kangsheng , Dong XiaoRong , Jin Faguang , Gao Hongjun , An Guangyu , Ding Cuimin , Jiang Xiaodong , Xiong Jianping , Zhou Xiangdong , Hu Sheng , Lu Ping , Liu Anwen , Guo Shuliang , Huang Jianjin , Zhu Chengchu , Zhao Jian , Gao Beili , Chen Yinglan , Hu Chengping , Zhang Jian , Zhang Hongmei , Zhao Hui , Wang Zhigao , Ma Xinjing , Shi Wei
Published: November 2024

Background

CameL phase 3 study demonstrated the superiority of camrelizumab plus chemotherapy over chemotherapy alone for progression-free survival in patients with previously untreated advanced non-squamous non-small-cell lung cancer (NSCLC) withoutEGFR/ALKalterations. Here, we present the 5-year outcomes.

Methods

Patients were randomized (1:1) and received 4–6 cycles of camrelizumab plus carboplatin and pemetrexed (n=205) or carboplatin and pemetrexed (n=207) every 3 weeks, followed by maintenance camrelizumab plus pemetrexed or pemetrexed only. Crossover from chemotherapy group to camrelizumab monotherapy was permitted after disease progression.

Results

Median time from randomization to data cut-off was 65.2 months (range, 59.7–72.2). HR for overall survival (OS) was 0.74 (95% CI 0.58 to 0.93; one-sided p=0.0043), and was 0.62 (95% CI 0.49 to 0.79; one-sided p<0.0001) after adjustment for crossover. Five-year OS rates were 31.2% (95% CI 24.7% to 37.9%) with camrelizumab plus chemotherapy versus 19.3% (95% CI 13.9% to 25.3%) with chemotherapy alone. Among the 33 patients who completed 2 years of camrelizumab, 5-year OS rate was 84.3% (95% CI 66.4% to 93.2%), and 5-year duration of response rate was 46.5% (95% CI 24.9% to 65.6%) in the 32 responders. No new safety signals were noted.

Conclusions

Camrelizumab plus carboplatin and pemetrexed as first-line therapy continued to demonstrate long-term OS benefit over carboplatin and pemetrexed, with manageable toxicity. Patients who completed 2 years of camrelizumab had enduring response and impressive OS. Current 5-year updated analysis further supports camrelizumab plus carboplatin and pemetrexed as a standard-of-care for previously untreated advanced non-squamous NSCLC withoutEGFR/ALKalterations.

Trial registration number

NCT03134872.
B cell c-Maf signaling promotes tumor progression in animal models of pancreatic cancer and melanoma
Authors: Zhong Qian , Hao Hongying , Li Shu , Ning Yongling , Li Hong , Hu Xiaoling , McMasters Kelly M , Yan Jun , Ding Chuanlin
Published: November 2024

Background

The role of B cells in antitumor immunity remains controversial, with studies suggesting the protumor and antitumor activity. This controversy may be due to the heterogeneity in B cell populations, as the balance among the subtypes may impact tumor progression. The immunosuppressive regulatory B cells (Breg) release interleukin 10 (IL-10) but only represent a minor population. Additionally, tumor-specific antibodies (Abs) also exhibit antitumor and protumor functions dependent on the Ab isotype. Transcription factor c-Maf has been suggested to contribute to the regulation of IL-10 in Breg, but the role of B cell c-Maf signaling in antitumor immunity and regulating Ab responses remains unknown.

Methods

Conditional B cell c-Maf knockout (KO) and control mice were used to establish a KPC pancreatic cancer model and B16.F10 melanoma model. Tumor progression was evaluated. B cell and T cell phenotypes were determined by flow cytometry, mass cytometry, and cytokine/chemokine profiling. Differentially expressed genes in B cells were examined by using RNA sequencing (RNA-seq). Peripheral blood samples were collected from healthy donors and patients with melanoma for B cell phenotyping.

Results

Compared with B cells from the spleen and lymph nodes (LN), B cells in the pancreas exhibited significantly less follicular phenotype and higher IL-10 production in naïve mice. c-Maf deficiency resulted in a significant reduction of CD9+IL-10-producing Breg in the pancreas. Pancreatic ductal adenocarcinoma (PDAC) progression resulted in the accumulation of circulating B cells with the follicular phenotype and less IL-10 production in the pancreas. Notably, B cell c-Maf deficiency delayed PDAC tumor progression and resulted in proinflammatory B cells. Further, tumor volume reduction and increased effective T cells in the tumor-draining LN were observed in B cell c-Maf KO mice in the B16.F10 melanoma model. RNA-seq analysis of isolated B cells revealed that B cell c-Maf signaling modulates immunoglobulin-associated genes and tumor-specific Ab production. We furthermore demonstrated c-Maf-positive B cell subsets and an increase of IL-10-producing B cells after incubation with IL-4 and CD40L in the peripheral blood of patients with melanoma.

Conclusion

Our study highlights that B cell c-Maf signaling drives tumor progression through the modulation of Breg, inflammatory responses, and tumor-specific Ab responses.
Genetic and therapeutic heterogeneity shape the baseline and longitudinal immune ecosystem of ovarian clear cell carcinoma
Authors: Xia Siyu , Chen Lihua , Yu Min , Li Jiana , Chen Jiaxin , Xu Fei , Ni Mengdong , Liu Chaohua , Wu Xiaohua , Chen Xiaojun , Li Jiajia
Published: November 2024

Background

Ovarian clear cell carcinoma (OCCC) is a rare and chemo-resistant subtype of ovarian cancer. While immunotherapy has demonstrated effectiveness in some OCCC cases, the mechanisms for heterogeneous immunoreactivity and potential combinatory strategies remain unclear.

Methods

Tumor samples from 13 patients with OCCC underwent single-cell mRNA-seq and TCR-seq to generate 1 40 683 cells transcriptome, while additionally 31 formalin-fixed paraffin-embedded samples were used for immunohistochemistry. Spatial transcriptomics of two OCCC samples and bulk RNA-seq of 58 patients were incorporated for spatial and interpatient level explorations. Serum tumor markers and radiologic images of three patients with OCCC who received combinatory VEGF and PD-1 inhibition were retrospectively analyzed.

Results

OCCC exhibited a dynamic immune architecture shaped by genetic and therapeutic pressure.ARID1Amutation linked to baseline immune activation, correlated with an enrichment of neoantigen-reactive CXCL13+CTLA4+CD8+T cells (p<0.001) and enhanced FASLG–FAS interactions. Recurrent OCCC was fibrotic, angiogenic, and immunosuppressive, exhibiting metabolic reprogramming towards activated activity in fatty acid metabolism. High CD36 (log-rank p=0.012, HR: 4.515) and CD47 expression (log-rank p=0.037, HR: 3.246) indicated worse progression-free survival. Treatment with bevacizumab increased intratumoral T cell infiltration and activated T cell interferon-γ signaling. Retrospective analysis of clinical cases revealed that combination therapy with anti-VEGF (vascular endothelial growth factor) and anti-PD-1 agents exerted clinical benefits in patients with OCCC with persistent, recurrent, and metastatic disease.

Conclusions

ARID1Amutation correlated with OCCC baseline immune activation. Stromal reconstruction and tumor metabolic reprogramming functioned as key processes of OCCC dynamic progression. VEGF inhibition remodeled OCCC stroma, restored T cell function and potentiated immunotherapy. CD36 and CD47 might be potential therapeutic targets for recurrent OCCC.
Uncommon biphasic CAR-T expansion induces hemophagocytic lymphohistiocytosis-like syndrome and fatal multiple infections following BCMA CAR-T cell therapy: a case report
Authors: Yan Wenqiang , Xiong Yu , Lv Rui , Du Chenxing , Yu Tengteng , Zhang Shuaishuai , Sui Weiwei , Deng Shuhui , Xiao Jigang , Xu Yan , Zou Dehui , Qiu Lugui , An Gang
Published: November 2024

B-cell maturation antigen(BCMA)-directed chimeric antigen receptor (CAR)-T-cell therapy has significantly improved the treatment of relapsed or refractory multiple myeloma (MM). Nevertheless, the uncommon phenomenon of biphasic CAR-T cell expansion in vivo and its related severe toxicities have not been methodically described and studied. Herein, we report a case of patients with MM who experienced two CAR-T cell expansion peaks and subsequently developed multiple severe toxicities following BCMA CAR-T cell infusion. The first expansion peak occurred on Day 7, accompanied by grade 3 cytokine release syndrome. The second peak occurred on Day 28, associated with severe immune effector cell-associated hematotoxicity (ICAHT), immune effector-cell associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), and polymicrobial infections. Both ICAHT and IEC-HS were refractory to our standard treatments; however, human umbilical cord mesenchymal stem cell infusion exhibited some efficacy in improving cytopenia. Despite the administration of a broad-spectrum anti-infective regimen, cytomegalovirus viremia remained uncontrollable, resulting in the development of central nervous system infection, neurological symptoms, and ultimately death. Additionally, we also employed high-dimensional 33-color spectral flow cytometry to describe the dynamic changes in immune cell components and functions between the two expansion peaks. Collectively, this case provides novel insights into the biphasic CAR-T expansion and related immune effector cell-associated toxicities.
Degradation of PARP1 by MARCHF3 in tumor cells triggers cCAS-STING activation in dendritic cells to regulate antitumor immunity in hepatocellular carcinoma
Authors: Cao Jun , Su Bingbing , Zhang Chi , Peng Rui , Tu Daoyuan , Deng Qiangwei , Jiang Guoqing , Jin Shengjie , Wang Qian , Bai Dou-Sheng
Published: November 2024

Background

Resistance to immune checkpoint inhibitors (ICIs) significantly limits the efficacy of immunotherapy in patients with hepatocellular carcinoma (HCC). However, the mechanisms underlying immunotherapy resistance remain poorly understood. Our aim was to clarify the role of membrane-associated ring-CH-type finger 3 (MARCHF3) in HCC within the framework of anti-programmed cell death protein-1 (PD-1) therapy.

Methods

MARCHF3 was identified in the transcriptomic profiles of HCC tumors exhibiting different responses to ICIs. In humans, the correlation between MARCHF3 expression and the tumor microenvironment (TME) was assessed via multiplex immunohistochemistry. In addition, MARCHF3 expression in tumor cells and immune cell infiltration were assessed by flow cytometry.

Results

MARCHF3 was significantly upregulated in tumors from patients who responded to ICIs. Increased MARCHF3 expression in HCC cells promoted dendritic cell (DC) maturation and stimulated CD8+T-cell activation, thereby augmenting tumor control. Mechanistically, we identified MARCHF3 as a pivotal regulator of the DNA damage response. It directly interacted with Poly(ADP-Ribose) Polymerase 1 (PARP1) via K48-linked ubiquitination, leading to PARP1 degradation. This process promoted the release of double-strand DNA and activated cCAS-STING in DCs, thereby initiating DC-mediated antigen cross-presentation and CD8+T-cell activation. Additionally, ATF4 transcriptionally regulated MARCHF3 expression. Notably, the PARP1 inhibitor olaparib augmented the efficacy of anti-PD-1 immunotherapy in both subcutaneous and orthotopic HCC mouse models.

Conclusions

MARCHF3 has emerged as a pivotal regulator of the immune landscape in the HCC TME and is a potent predictive biomarker for HCC. Combining interventions targeting the DNA damage response with ICIs is a promising treatment strategy for HCC.
HNF-1β alleviates podocyte injury in lupus nephritis by maintaining endoplasmic reticulum homeostasis
Authors: Zou Hui-mei , Yu Jie , Ruan Yuan-yuan , Xie Ying , An Xiao-min , Chen Pei-lei , Luo Ying-qin , Shi Ming-jun , Liu Miao , Xu Li-fen , Liu Jun , Guo Bing , Zhang Fan
Published: November 2024

Objective

The current study aims to elucidate the critical function of hepatocyte nuclear factor 1-beta (HNF1-β) in lupus nephritis (LN) by investigating its modulation of the Derlin-1/valosin-containing protein (VCP)/VCP-interacting membrane selenoprotein (VIMP) complex, endoplasmic reticulum (ER) stress and podocyte apoptosis.

Methods

In vitro and in vivo models of LN were established using glomerular podocytes treated with LN serum and MRL/lpr mice, respectively. The expression levels of HNF1-β were analysed in kidney tissues from patients with LN and MRL/lpr mice. To assess the effects of HNF1-β inhibition, an adeno-associated virus vector carrying HNF1-β short hairpin was administered to MRL/lpr mice. In vitro, glomerular podocytes were transfected with HNF1-β small interfering RNA (siRNA) or HNF1-β overexpression plasmids to explore their regulatory effects on the Derlin-1/VCP/VIMP complex and podocyte apoptosis. Dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays were performed to investigate the transcriptional activation of Derlin-1 and VCP promoters by HNF1-β.

Results

A significant decrease in HNF1-β levels was observed in kidney tissues from patients with LN while MRL/lpr mice exhibited an initial compensatory increase followed by a subsequent decrease in renal HNF1-β expression. Overexpression of HNF1-β transcriptionally upregulated Derlin-1 and VCP mitigating LN serum-induced ER stress and podocyte apoptosis. In contrast, HNF1-β inhibition exacerbated renal dysfunction and structural damage in MRL/lpr mice. Interestingly, HNF1-β inhibition transcriptionally repressed ERP44, leading to calcium ions (Ca²+) release-mediated disruption and inactivation of the Derlin-1/VCP/VIMP complex. This finding suggests that HNF1-β not only regulates the expression of key proteins in the Derlin-1/VCP/VIMP complex but also influences their assembly through Ca²+release regulation.

Conclusion

This study provides novel insights into the regulatory mechanisms of HNF1-β in LN emphasising its impact on the Derlin-1/VCP/VIMP complex, ER stress and podocyte apoptosis. These findings have the potential to inform the development of new diagnostic tools and therapeutic strategies for LN.
Performance of the EULAR Systemic sclerosis Impact of Disease (ScleroID) questionnaire as a patient-reported outcome measure for patients with diffuse systemic sclerosis
Authors: Dobrota Rucsandra , Garaiman Alexandru , Fligelstone Kim , Tyrrell Kennedy Ann , Roennow Annelise , Allanore Yannick , Carreira Patricia E , Czirják László , Denton Chris , Hesselstrand Roger , Sandqvist Gunnel , Kowal-Bielecka Otylia , Bruni Cosimo , Matucci-Cerinic Marco , Mihai Carina , Gherghe Ana Maria , Mueller-Ladner Ulf , Kvien Tore , Heiberg Turid , Distler Oliver , Becker Mike Oliver
Published: November 2024

Objective

Systemic sclerosis Impact of Disease (ScleroID) is the first comprehensive patient-reported outcome measure (PROM) specifically developed for systemic sclerosis (SSc). We investigated the performance of ScleroID in patients with diffuse cutaneous SSc (dcSSc), as a prerequisite for its use in randomised controlled trials (RCTs) testing potentially disease-modifying drugs.

Methods

All patients with dcSSc from the large, multicentric, ScleroID cohort were included. SSc-Health Assessment Questionnaire (HAQ), EuroQol-5 Dimensions and 36-item Short Form Health Survey (SF-36) were used as comparators. The study includes a longitudinal arm with a reliability visit at 7±3 days and a 12 months follow-up visit. The performance of ScleroID in dcSSc was assessed according to the Outcome Measures in Rheumatology filter.

Results

In total, 152 dcSSc patients were analysed (29% male, median age 54 years). ScleroID reflected well the disease impact of dcSSc, showing a good construct validity with high Spearman’s correlation coefficients with comparators (SSc-HAQ, 0.79, 95% CI (0.69, 0.86); HAQ-Disability Index, 0.72 95% CI (0.60, 0.80); SF-36 physical score, −0.69 95% CI (−0.77, –0.60)). The internal consistency was strong (Cronbach’s alpha 0.87, split-half reliability coefficient 0.88).

In the longitudinal arm, 44 patients had a reliability visit and 113 had a follow-up visit, of whom 19/113 (17%) reported a significant change (11 improved, 8 worsened). ScleroID showed a good consistency and discriminative ability with excellent test–retest reliability (intraclass correlation coefficient 0.89, 95% CI (0.84, 0.92)) and moderate sensitivity to change (standardised response mean −0.63 in the improved subgroup and 0.48 in the worsened subgroup), but superior to the comparators.

Conclusion

The European Alliance of Associations for Rheumatology (EULAR) ScleroID performs well for patients with dcSSc. This supports its inclusion and regular assessment as PROM in RCTs.
A Decentralized Approach to Award Game Achievements
Authors: Bruschi Francesco , Sciuto Donatella , Paulon Tommaso , Marchesi Andrea
Published: November 2024

Blockchain technology has the potential to transform the gaming industry by enabling players to own in-game assets and receive NFTs or tokens as rewards for their accomplishments. However, one critical issue is determining how to ensure that achievement conditions are met (e.g., that the player completed level number ten). Current approaches either open cheating backdoors (e.g. if the client checks the conditions) or introduce centralization points and limitations (if a backend checks the condition). To overcome these problems a potential solution may seem to execute games directly on-chain, but the high computational cost (especially on Ethereum) and latency has made it impossible so far; however, the development of new technologies like proofs of computation enables new approaches. In this paper we employ succint proofs of computation to allow the player to
prove
to a smart contract on a blockchain that he reached (achieved) a certain state in an action game, that can then be played directly in the client; this allows to implement decentralized systems that can ensure fair and transparent rewarding. Moreover, we address the problem of proving that a certain game on the client has taken no more than a specific amount of time.
Analysing the Predictability of Language Model Performance
Authors: Schellaert Wout , Martínez-Plumed Fernando , Hernández-Orallo José
Published: November 2024

Can a language model predict for which questions
another
language model will answer successfully? We investigate the extent to which performance prediction is possible and dissect various factors that influence it. Our experimental setting fine-tunes DeBERTa models, which we call
assessors
, on the evaluation results of generative language models with up to 128 billion parameters, which we refer to as
subject systems
. Our analysis spans more than 100 tasks from BIG-bench. We find that the assessors can match and even exceed the subjects’ confidence in both refinement and calibration, anticipating failures at near perfect levels for some tasks. We also find that for performance prediction it can be beneficial to learn from the scores on multiple tasks or to learn from the scores of multiple subjects, but both depend on the task at hand. Lastly, we find that large and small subject systems are equally predictable, showing promise for the scalability of the predictability problem.
Review—Exploring Emerging Materials for Memristor Fabrication: A Review of Recent Progress
Authors: Saini Mohit Kumar , Khosla Mamta , Raj Balwinder
Published: November 2024

This paper presents a comprehensive analysis of various materials employed in fabrication of memristor devices, including transition metal oxides (also known as Binary oxides), low dimension materials (two-dimensional materials), perovskite materials, organic compounds, etc. The fabrication methods, properties, and impact on device performance for different material categories are also discussed. The paper covers the significance of materials in memristor technology and explores specific examples of transition metal oxides, organic materials, and two-dimensional materials. Furthermore, the review discusses challenges related to stability, compatibility with complementary metal oxide semiconductor technology, and the need for understanding the different phenomena of formation and rupturing of filament which governs the memristor mechanisms and underlying physics. The paper also emphasizes opportunities for future research, such as stability enhancement, neuromorphic computing applications, and the discoveries of novel materials and their concepts. This review will provide a comprehensive summary to the researchers making efforts to understand various materials and their fundamental properties in the fabrication of memristors and their potential for use in practical applications.
Hydraulic System Fault Diagnosis Based on Dual‐Channel Convolutional Neural Network and Improved D‐S Evidence Theory
Authors: Qi Jiyang , Qi Yue , Luo Shenghua , Zhang Jiahao
Published: November 2024

To address the problem that the traditional convolutional neural network (CNN) cannot fully extract the fault feature information in a single channel and the accuracy of hydraulic system fault diagnosis based on a single signal is not high, a fault diagnosis method combining dual‐channel CNN and improved D‐S evidence theory is proposed. First, the pressure signal, temperature signal, and vibration signal are denoised using the wavelet threshold denoising method, and the denoised pressure signal, temperature signal, and vibration signal are put into two channels for feature extraction, respectively. One channel uses 1D‐CNN to extract the features, and the other channel uses an improved HHT to process the input signal to obtain the time‐frequency map and then uses 2D‐CNN to extract the features, and finally, the features of the two channels are concatenated for fault diagnosis. The fault diagnosis results based on the denoised pressure signal, temperature signal, and vibration signal, respectively, are used as three pieces of evidence, the similarity coefficients of each evidence are obtained by calculating the value similarity and direction similarity between the evidences, the weight of each evidence is calculated based on the similarity, the new evidence is gained by the weighted average method to replace the most conflicting evidence, and information fusion based on the improved D‐S evidence theory is performed to determine the cause of the fault. Finally, the experiments are conducted based on the hydraulic system fault dataset, and the experimental results show that the accuracy of the hydraulic system fault diagnosis using this method reaches 99.75%, which is 7.0%, 7.5%, and 6.5% higher than the results of the fault diagnosis based on a single pressure signal, temperature signal, and vibration signal, respectively. The proposed method improves the accuracy of fault diagnosis and has some application value.
Co-occurrence of two rare diseases: a child with phenylketonuria and WNT1 osteoporosis
Authors: Doulgeraki Artemis , Wang Fan , Skouma Anastasia , Petropoulou Eleana , Tournis Symeon , Costantini Alice , Mäkitie Outi
Published: November 2024

Introduction: Phenylketonuria (PKU), an inborn error of metabolism, when inadequately treated, may lead to nutritional deficits, which could affect bone health. This remains a controversial issue, given that in the majority of PKU cases, bone mineral density is within normal limits. On the other hand, WNT1 mutations are detrimental for bone, as they lead to primary osteoporosis.
Case presentation: We present an eleven year-old girl under a very strict diet for phenylketonuria (i.e. with low phenylalanine levels) and severe osteoporosis, signified by the presence of multiple vertebral fractures, which could not be attributed to her inborn error of metabolism. Family screening, including bone densitometry revealed unexplained osteoporosis in her father and brother. Further genetic work up revealed a new WNT1, disease-causing mutation. The patient’s dietary plan was modified, in order to achieve better metabolic control and she was given vitamin D and calcium supplements. These measures led to great clinical and radiological improvement, without the use of bisphosphonates.
Conclusion: In a patient with a chronic disorder known to affect the skeleton, the presence of disproportionally severe osteoporosis should prompt further diagnostic work up, in order to explain the severe bone phenotype, thus enabling more efficient and targeted therapeutic interventions.
Characteristics of patients with anaphylaxis to European hornet (Vespa crabro) venom compared to anaphylaxis to wasp (Vespula spp.) venom in southern Germany
Authors: Bertlich Mattis , Weber Felix , Bertlich Ines , Kendziora Benjamin , Rueff Franziska , Spiegel Jennifer L. , French Lars E. , Oppel Eva
Published: November 2024

Background: Systemic hypersensitivity to hymenoptera species venom is the most common cause for anaphylaxis in adults. Due to similarities between hornet (Vespa crabro) and wasp (Vespula spp.) venom, patients with hornet venom anaphylaxis are often treated similarly to wasp-allergic patients. However, comparative data are scarce. This study aimed to analyze differences and similarities between these two groups.

Methods: A retrospective analysis with 42 patients with certain anaphylaxis to hornet venom was conducted. These were matched for age, gender, and CAP-class with 42 patients with wasp venom anaphylaxis. Clinical outcomes and treatment adherence were compared.

Results: Patients with hornet venom anaphylaxis showed a significantly higher degree of anaphylaxis (21 vs 9 patients with °III/IV anaphylaxis, p<0.001), despite similar tryptase-levels (6.3±8.3 vs. 5.1±4.2) or presence of mastocytosis (2 vs. 3). These patients also showed significantly lower therapy adherence, resulting in fewer patients undergoing specific immune therapy (29 vs. 37, p=0.030) or sting challenges (14 vs. 27, p=0.046). Both groups showed high efficacy of specific immunotherapy with wasp venom extract.

Conclusion: Hornet stings induce more severe anaphylaxis, while patients with hornet venom allergies demonstrate lower treatment compliance, likely due to inadequate education. Specific immunotherapy with wasp venom extract remains effective for both.