bluuebunny/crossref_metadata_2025 huggingface dataset:
RNA 2'-O-methylation promotes persistent R-loop formation and AID-mediated IgH class switch recombination
Authors: Kassab Muzaffer Ahmad , Chen Yibin , Wang Xin , He Bo , Brown Eric J. , Yu Xiaochun
Published: July 2024

Background

RNA–DNA hybrids or R-loops are associated with deleterious genomic instability and protective immunoglobulin class switch recombination (CSR). However, the underlying phenomenon regulating the two contrasting functions of R-loops is unknown. Notably, the underlying mechanism that protects R-loops from classic RNase H-mediated digestion thereby promoting persistence of CSR-associated R-loops during CSR remains elusive.

Results

Here, we report that during CSR, R-loops formed at the immunoglobulin heavy (IgH) chain are modified by ribose 2′-O-methylation (2′-OMe). Moreover, we find that 2′-O-methyltransferase fibrillarin (FBL) interacts with activation-induced cytidine deaminase (AID) associated snoRNA aSNORD1C to facilitate the 2′-OMe. Moreover, deleting AID C-terminal tail impairs its association with aSNORD1C and FBL. Disrupting FBL, AID or aSNORD1C expression severely impairs 2′-OMe, R-loop stability and CSR. Surprisingly, FBL, AID’s interaction partner and aSNORD1C promoted AID targeting to the IgH locus.

Conclusion

Taken together, our results suggest that 2′-OMe stabilizes IgH-associated R-loops to enable productive CSR. These results would shed light on AID-mediated CSR and explain the mechanism of R-loop-associated genomic instability.
A longitudinal multi-centric cohort study assessing infant neurodevelopment delay among women with persistent postpartum depression in Nepal
Authors: KC Ashish , Chandna Jaya , Acharya Ankit , Gurung Rejina , Andrew Carin , Skalkidou Alkistis
Published: July 2024

Background

Infant neurodevelopment in the first years after birth is determined by multiple factors, including parental care and maternal mental wellbeing. In this study, we aim to assess the impact of persistent maternal depressive symptoms during the first 3 months postpartum on infant neurodevelopment at 6 months.

Methods

Using a longitudinal cohort design, 1253 mother-infant pairs were followed up at 7, 45, and 90 days to assess postpartum depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS); infants were followed up at 6 months to assess neuro-developmental status using the WHO’s Infant and Young Child Development (IYCD) tool. A generalized linear regression model was used to assess the association between persistent postpartum depressive symptoms and infant neurodevelopmental delay at 6 months. A generalized linear mixed model (GLMM) with a hospital as a random intercept was used to assess the persistent postpartum depressive symptoms with an IYCD score. Linear regression was used to compare the IYCD scores between exposure groups.

Results

In the study population, 7.5% of mothers had persistent depressive symptoms, and 7.5% of infants had neurodevelopmental delay. Infants born to mothers with persistent depressive symptoms had a higher proportion of neurodevelopmental delay than infants born to women without persistent symptoms (48.6% vs 5.1%; p < 0.001). In the adjusted regression model, infants whose mothers had persistent depressive symptoms at 7, 45, and 90 days had a 5.21-fold increased risk of neurodevelopmental delay (aRR, 5.21; 95% CI, 3.17, 8.55). Mean scores in the motor domain (12.7 vs 15.2; p < 0.001) and language domain (6.4 vs 8.5; p < 0.001) were significant when a mother had persistent depression vs. no depression. Mean scores in the general behavioral domain (5.9 vs 10.4, p < 0.001) and the socio-emotional domain (15.4 vs 17.7; p < 0.001) were significantly different when a mother had persistent depression vs no persistent depression.

Conclusions

Our results suggest that 6-month-old infants are at higher risk for neurodevelopment delays if their mother reports persistent symptoms of depression from 7 to 90 days postpartum. The neurodevelopmental delay can be observed in all functional domains. Preventive intervention to reduce maternal postpartum depression may reduce the impact on infant developmental delay.
A diagnostic model for Parkinson’s disease based on circadian rhythm-related genes
Authors: Wang Lufeng , Bao Yiwen , Duan Xiaofan , Li Hongxia , Ding Hao , Yu Fei , yang Jie , Hu Yongbo , Huang Dongya
Published: July 2024

Background

Circadian rhythm (CR) disturbance is intricately associated with Parkinson’s disease (PD). However, the involvement of CR-related mechanisms in the pathogenesis and progression of PD remains elusive.

Methods

A total of 141 PD patients and 113 healthy participants completed CR-related clinical examinations in this study. To further investigate the CR-related mechanisms in PD, we obtained datasets (GSE7621, GSE20141, GSE20292) from the Gene Expression Omnibus database to identify differentially expressed genes between PD patients and healthy controls and further selected CR-related genes (CRRGs). Subsequently, the least absolute shrinkage and selection operator (LASSO) followed by logistic algorithms were employed to identify the hub genes and construct a diagnostic model. The predictive performance was evaluated by area under the curve (AUC), calibration curve, and decision curve analyses in the training set and external validation sets. Finally, RT‒qPCR and Western blotting were conducted to verify the expression of these hub genes in blood samples. In addition, Pearson correlation analysis was utilized to validate the association between expression of hub genes and circadian rhythm function.

Results

Our clinical observational study revealed that even early-stage PD patients exhibited a higher likelihood of experiencing sleep disturbances, nocturnal hypertension, reverse-dipper blood pressure, and reduced heart rate variability compared to healthy controls. Furthermore, 4 CR-related hub genes (AGTR1, CALR, BRM14, and XPA) were identified and subsequently incorporated as candidate biomarkers to construct a diagnostic model. The model showed satisfactory diagnostic performance in the training set (AUC = 0.941), an external validation set GSE20295 (AUC = 0.842), and our clinical centre set (AUC = 0.805). Additionally, the up-regulation of CALR, BRM14 and the down-regulation of AGTR1, XPA were associated with circadian rhythm disruption.

Conclusion

CR disturbance seems to occur in the early stage of PD. The diagnostic model based on CR-related genes demonstrated robust diagnostic efficacy, offering novel insights for future clinical diagnosis of PD and providing a foundation for further exploration into the role of CR-related mechanisms in the progression of PD.
Uncovering molecular features driving lung adenocarcinoma heterogeneity in patients who formerly smoked
Authors: Wang Peiyao , Ng Raymond , Lam Stephen , Lockwood William W.
Published: July 2024

Background

An increasing proportion of lung adenocarcinoma (LUAD) occurs in patients even after they have stopped smoking. Here, we aimed to determine whether tobacco smoking induced changes across LUADs from patients who formerly smoked correspond to different biological and clinical factors.

Methods

Random forest models (RFs) were trained utilizing a smoking associated signature developed from differentially expressed genes between LUAD patients who had never smoked (NS) or currently smoked (CS) from TCGA (n = 193) and BCCA (n = 69) cohorts. The RFs were subsequently applied to 299 and 131 formerly smoking patients from TCGA and MSKCC cohorts, respectively. FS were RF-classified as either CS-like or NS-like and associations with patient characteristics, biological features, and clinical outcomes were determined.

Results

We elucidated a 123 gene signature that robustly classified NS and CS in both RNA-seq (AUC = 0.85) and microarray (AUC = 0.92) validation test sets. The RF classified 213 patients who had formerly smoked as CS-like and 86 as NS-like from the TCGA cohort. CS-like and NS-like status in formerly smoking patients correlated poorly with patient characteristics but had substantially different biological features including tumor mutational burden, number of mutations, mutagenic signatures and immune cell populations. NS-like formerly smoking patients had 17.5 months and 18.6 months longer overall survival than CS-like patients from the TCGA and MSKCC cohorts, respectively.

Conclusions

Patients who had formerly smoked with LUAD harbor heterogeneous tumor biology. These patients can be divided by smoking induced gene expression to inform prognosis and underlying biological characteristics for treatment selection.
Neural basis of lower-limb visual feedback therapy: an EEG study in healthy subjects
Authors: Adham Ahmed , Le Ba Thien , Bonnal Julien , Bessaguet Hugo , Ojardias Etienne , Giraux Pascal , Auzou Pascal
Published: July 2024

Background

Video-feedback observational therapy (VOT) is an intensive rehabilitation technique based on movement repetition and visualization that has shown benefits for motor rehabilitation of the upper and lower limbs. Despite an increase in recent literature on the neurophysiological effects of VOT in the upper limb, there is little knowledge about the cortical effects of visual feedback therapies when applied to the lower limbs. The aim of our study was to better understand the neurophysiological effects of VOT. Thus, we identified and compared the EEG biomarkers of healthy subjects undergoing lower limb VOT during three tasks: passive observation, observation and motor imagery, observation and motor execution.

Methods

We recruited 38 healthy volunteers and monitored their EEG activity while they performed a right ankle dorsiflexion task in the VOT. Three graded motor tasks associated with action observation were tested: action observation alone (O), motor imagery with action observation (OI), and motor execution synchronized with action observation (OM). The alpha and beta event-related desynchronization (ERD) and event-related synchronization (or beta rebound, ERS) rhythms were used as biomarkers of cortical activation and compared between conditions with a permutation test. Changes in connectivity during the task were computed with phase locking value (PLV).

Results

During the task, in the alpha band, the ERD was comparable between O and OI activities across the precentral, central and parietal electrodes. OM involved the same regions but had greater ERD over the central electrodes. In the beta band, there was a gradation of ERD intensity in O, OI and OM over central electrodes. After the task, the ERS changes were weak during the O task but were strong during the OI and OM (Cz) tasks, with no differences between OI and OM.

Conclusion

Alpha band ERD results demonstrated the recruitment of mirror neurons during lower limb VOT due to visual feedback. Beta band ERD reflects strong recruitment of the sensorimotor cortex evoked by motor imagery and action execution. These results also emphasize the need for an active motor task, either motor imagery or motor execution task during VOT, to elicit a post-task ERS, which is absent during passive observation.

Trial Registration NCT05743647
Biomechanically based Fu’s subcutaneous needling treatment for senile knee osteoarthritis: protocol for a randomized controlled trial
Authors: Huang Hai , Liu Ruixuan , Shao Jieying , Chen Shiyang , Sun Jian , Zhu Junxia
Published: July 2024

Introduction

Fu’s subcutaneous needling (FSN) is a new type of acupuncture that uses subcutaneous tissue to oscillate from side to side to improve muscle pathology status and can be effective in treating Knee osteoarthritis. Nonetheless, whether the clinical effect is similar to that of most commonly used drugs is unclear. Thus, this study aims to determine the pain-relieving effect and improvement in the joint function of the FSN therapy by comparing it with that of a positive control drug (celecoxib). Furthermore, this clinical trial also aims to evaluate the effect of FSN on gait and lower limb muscle flexibility, which can further explore the scientific mechanisms of the FSN therapy.

Methods and analysis

This study is a randomized, parallel-controlled, single-center prospective clinical study that includes 60 participants, with an FSN group (n = 30) and a drug group (n = 30). The Fu’s subcutaneous needling (FSN) group undergo the FSN therapy 3 times a week for 2 weeks, while the drug group receives 0.2 g/day oral celecoxib for 2 weeks, with a follow-up period of 4 weeks after the completion of treatment. The primary outcome is the difference in the visual analog scale score after 2 weeks of treatment compared with baseline. The Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index, joint active range of motion test, three-dimensional gait analysis, and shear wave elastic imaging technology analysis in lower limb muscles are also performed to demonstrate clinical efficacy.

Ethics and dissemination

The trial is performed following the Declaration of Helsinki. The study protocol and consent form have been approved by the Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine. All patients will give informed consent before participation and the trial is initiated after approval. The results of this trial will be disseminated through publication in peer-reviewed journals.

Trial registration number: NCT06328153.
Is still effective massive allograft reconstruction in parosteal osteosarcoma of the distal femur? Review of the literature and advantages of newer technologies
Authors: Pala Elisa , Canapeti Joele , Trovarelli Giulia , Angelini Andrea , Ruggieri Pietro
Published: July 2024

Purpose

Parosteal Osteosarcoma is a well-differentiated, low-grade bone sarcoma. It most commonly occurs in the third decade of life, usually in the distal femur. This study aims to perform a literature review about the types of reconstructions reported and to analyze the results of an updated technique of resection using custom-made 3D-printed cutting guides.

Methods

We perform a systematic literature review about parosteal osteosarcoma, evaluating treatments, margins, local recurrence, complications, and functional results when available. We also report a case treated in our Center with a revisited technique introducing custom-made 3D-printed cutting guides.

Results

We analyzed 12 studies with a total of 151 patients. The distal femur was the most frequently reported site (81.5%). After distal femur resection, reconstruction was performed with graft in most cases (48%), followed by prosthetic reconstruction (40%). Margins were wide in 85.5% of cases. The total incidence of local recurrence was 11%. Functional results were excellent in all cases, with a mean MSTS score of 86%. In our case, with the help of the jigs, the surgical technique was relatively easy, graft fusion excellent and fast, margins wide, and functional results excellent.

Conclusions

In the literature, the most commonly used type of reconstruction after resection is biological with graft. Indeed, despite the increasing number of prosthetic reconstructions, the historical diaphysometaphyseal hemiresection and graft is still indicated in parosteal osteosarcoma of the distal femur. New technologies, such as the jigs we used, allow significant advantages during the procedure: reduce the resection and graft preparation time, allow a better match between components, and help to obtain safer margins, sparing as much bone as possible.
Effect of flow-optimized pressure control ventilation-volume guaranteed (PCV-VG) on postoperative pulmonary complications: a consort study
Authors: Sun Ting Ting , Chen Ke Xin , Tao Yong , Zhang Gong Wei , Zeng Li , Lin Min , Huang Jing , Hu Yue
Published: July 2024

Background

Postoperative pulmonary complications (PPCs) after one-lung ventilation (OLV) significantly impact patient prognosis and quality of life.

Objective

To study the impact of an optimal inspiratory flow rate on PPCs in thoracic surgery patients.

Methods

One hundred eight elective thoracic surgery patients were randomly assigned to 2 groups in this consort study (control group: n = 53 with a fixed inspiratory expiratory ratio of 1:2; and experimental group [flow rate optimization group]: n = 55). Measurements of Ppeak, Pplat, PETCO2, lung dynamic compliance (Cdyn), respiratory rate, and oxygen concentration were obtained at the following specific time points: immediately after intubation (T0); immediately after starting OLV (T1); 30 min after OLV (T2); and 10 min after 2-lung ventilation (T4). The PaO2:FiO2 ratio was measured using blood gas analysis 30 min after initiating one-lung breathing (T2) and immediately when OLV ended (T3). The lung ultrasound score (LUS) was assessed following anesthesia and resuscitation (T5). The occurrence of atelectasis was documented immediately after the surgery. PPCs occurrences were noted 3 days after surgery.

Results

The treatment group had a significantly lower total prevalence of PPCs compared to the control group (3.64% vs. 16.98%; P = 0.022). There were no notable variations in peak airway pressure, airway plateau pressure, dynamic lung compliance, PETCO2, respiratory rate, and oxygen concentration between the two groups during intubation (T0). Dynamic lung compliance and the oxygenation index were significantly increased at T1, T2, and T4 (P < 0.05), whereas the CRP level and number of inflammatory cells decreased dramatically (P < 0.05).

Conclusion

Optimizing inspiratory flow rate and utilizing pressure control ventilation -volume guaranteed (PCV-VG) mode can decrease PPCs and enhance lung dynamic compliance in OLV patients.
Prevalence of common mental disorder and its association with perceived stigma and social support among people living with HIV/AIDS in Ethiopia: a systematic review and meta-analysis
Authors: Duko Bereket , Belayhun Yitagesu , Bedaso Asres
Published: July 2024

Background

When common mental disorders (CMD) co-occur with HIV/AIDS, they can complicate patient diagnosis, help-seeking behaviors, quality of life, treatment outcomes, and drug adherence. Thus, estimating the pooled prevalence of CMD and its association with perceived stigma and social support among people living with HIV/AIDS (PLWHA) in Ethiopia could potentially support policymakers and health professionals to understand the disease burden and set a solution to improve the mental well-being of PLWHA.

Methods

Popular databases such as PubMed, SCOPUS, EMBASE, and Psych-INFO as well as Google Scholar, AJOL, CINAHL, PILOTS and Web of Science were searched for the relevant articles conducted in Ethiopia. We included cross-sectional, case–control, and cohort studies in the review. The Comprehensive Meta-Analysis software version 3.0 was used to pool the results of the included studies. The Q- and I2-statistics were used to assess the heterogeneity between the included studies. We employed a random-effects meta-analysis model to estimate the pooled prevalence of CMD and to account for heterogeneity among the included studies. We also conducted a leave-one-out analyses, and stratified meta-analyses by gender (male and female).

Results

The studies included in this systematic review and meta-analysis were published between 2009 and 2021, recruiting a total of 5625 participants. The pooled estimated prevalence of CMD among PLWHA in Ethiopia was 26.1% (95% CI 18.1–36.0). The pooled estimated prevalence of CMD was significantly higher among females, at 39.5% (95% CI 21.2–39.0), compared to males, 26.9% (95% CI 15.6–31.7). Moreover, the pooled estimated prevalence of CMD in PLWHA ranged from 23.5 to 28.9% in the leave-one-out sensitivity analysis, indicating that the removal of any single study did not significantly affect the pooled estimate. The pooled effects (AOR) of Perceived HIV stigma and poor perceived social support on common mental disorder were 2.91, 95% CI (1.35–6.29) and 5.56, 95% CI (1.89–16.39), respectively.

Conclusion

People living with HIV/AIDS (PLWHA) who received poor social support and those with HIV-related perceived stigma were found to have strong association with CMD. Therefore, it is advisable that all PLWHA attending ART clinic should be screened for CMD, social support and HIV-related perceived stigma.
Unlocking the diagnostic power of plasma extracellular vesicle miR-200 family in pancreatic ductal adenocarcinoma
Authors: Liu Daniel S.K. , Puik Jisce R. , Patel Bhavik Y. , Venø Morten T. , Vahabi Mahrou , Prado Mireia Mato , Webber Jason P. , Rees Eleanor , Upton Flora M. , Bennett Kate , Blaker Catherine , Immordino Benoit , Comandatore Annalisa , Morelli Luca , Sivakumar Shivan , Swijnenburg Rutger-Jan , Besselink Marc G. , Jiao Long R. , Kazemier Geert , Giovannetti Elisa , Krell Jonathan , Frampton Adam E.
Published: July 2024

Background

Distinguishing benign from malignant pancreaticobiliary disease is challenging because of the absence of reliable biomarkers. Circulating extracellular vesicles (EVs) have emerged as functional mediators between cells. Their cargos, including microRNAs (miRNAs), are increasingly acknowledged as an important source of potential biomarkers. This multicentric, prospective study aimed to establish a diagnostic plasma EV-derived miRNA signature to discriminate pancreatic ductal adenocarcinoma (PDAC) from benign pancreaticobiliary disease.

Methods

Plasma EVs were isolated using size exclusion chromatography (SEC) and characterised using nanoparticle tracking analysis, electron microscopy and Western blotting. EV-RNAs underwent small RNA sequencing to discover differentially expressed markers for PDAC (n = 10 benign vs. 10 PDAC). Candidate EV-miRNAs were then validated in a cohort of 61 patients (n = 31 benign vs. 30 PDAC) by RT-qPCR. Logistic regression and optimal thresholds (Youden Index) were used to develop an EV-miR-200 family model to detect cancer. This model was tested in an independent cohort of 95 patients (n = 30 benign, 33 PDAC, and 32 cholangiocarcinoma).

Results

Small RNA sequencing and RT-qPCR showed that EV-miR-200 family members were significantly overexpressed in PDAC vs. benign disease. Combined expression of the EV-miR-200 family showed an AUC of 0.823. In an independent validation cohort, application of this model showed a sensitivity, specificity and AUC of 100%, 88%, and 0.97, respectively, for diagnosing PDAC.

Conclusions

This is the first study to validate plasma EV-miR-200 members as a clinically-useful diagnostic biomarker for PDAC. Further validation in larger cohorts and clinical trials is essential. These findings also suggest the potential utility in monitoring response and/or recurrence.

Graphical Abstract
Clinical application of targeted next-generation sequencing in severe pneumonia: a retrospective review
Authors: Zhang Peng , Liu Baoyi , Zhang Shuang , Chang Xuefei , Zhang Lihe , Gu Dejian , Zheng Xin , Chen Jiaqing , Xiao Saiyin , Wu Zhentao , Cai Xuemin , Long Mingfa , Lu Wenjie , Zheng Mingzhu , Chen Rongrong , Gao Rui , Zheng Yan , Wu Jinhua , Feng Qiujuan , He Gang , Chen Yantang , Zheng Weihao , Zuo Wanli , Huang Yanming , Zhang Xin
Published: July 2024

Background

The precise identification of the underlying causes of infectious diseases, such as severe pneumonia, is essential, and the development of next-generation sequencing (NGS) has enhanced the effectiveness of pathogen detection. However, there is limited information on the systematic assessment of the clinical use of targeted next-generation sequencing (tNGS) in cases of severe pneumonia.

Methods

A retrospective analysis was conducted on 130 patients with severe pneumonia treated in the ICU from June 2022 to June 2023. The consistency of the results of tNGS, metagenomics next-generation sequencing (mNGS), and culture with the clinical diagnosis was evaluated. Additionally, the results for pathogens detected by tNGS were compared with those of culture, mNGS, and quantitative reverse transcription PCR (RT-qPCR). To evaluate the efficacy of monitoring severe pneumonia, five patients with complicated infections were selected for tNGS microbiological surveillance. The tNGS and culture drug sensitisation results were then compared.

Results

The tNGS results for the analysis of the 130 patients showed a concordance rate of over 70% with clinical diagnostic results. The detection of pathogenic microorganisms using tNGS was in agreement with the results of culture, mNGS, and RT-qPCR. Furthermore, the tNGS results for pathogens in the five patients monitored for complicated infections of severe pneumonia were consistent with the culture and imaging test results during treatment. The tNGS drug resistance results were in line with the drug sensitivity results in approximately 65% of the cases.

Conclusions

The application of tNGS highlights its promise and significance in assessing the effectiveness of clinical interventions and providing guidance for anti-infection therapies for severe pneumonia.
Prevalence of supplement usage and related attitudes and reasons among fitness athletes in the gyms of Kashan and its relationship with feeding behavior: a cross-sectional study
Authors: Moradi Fatemeh , Yazdani Akram , Nematolahi Faezeh , Hosseini-Roknabadi Seyed Mohammad , Sharifi Nasrin
Published: July 2024

Background

The overuse of supplements among athletes is a widespread issue affecting the health of both male and female athletes. However, research on supplements usage among female fitness athletes is limited, and there is little information on the feeding behavior of fitness athletes who use supplements. This study aimed to fill the gap in knowledge by examining the prevalence of supplement usage and its related attitudes and reasons among fitness athletes in the gyms of Kashan. It further aimed to investigate the correlation between supplements usage and the feeding behavior of fitness athletes.

Methods

For these purposes, in this cross-sectional study, 433 fitness athletes (15‒46 years old) in 28 gyms in the city of Kashan were surveyed using a researcher-made questionnaire in 2023. Five experts confirmed the validity of the questionnaire. The present study considered the supplements based on the Australian Institute of Sport position statement. A Chi-square analysis was conducted to examine the relationship between the study variables and supplement usage.

Results

Overall, 272 male and 161 female fitness athletes participated in this study. The results revealed that 57.9% of participants used supplements, most commonly vitamin C, vitamin D, omega-3 fatty acids, and whey protein. The main reason for using supplements was to speed up body repair after exercise (69.5%). Additionally, 41.8% of these athletes believed that using supplements improves their overall performance, and 21.9% thought that supplements do not harm the body. Moreover, a correlation was observed between feeding behavior and the consumption of supplements. It was found that athletes who use supplements tend to eat more white meat, seeds, and nuts and fewer high-fat dairy products than those who do not consume them.

Conclusion

Using supplements among fitness athletes in the gyms of Kashan is common. The main reason for using these substances was to speed up body repair after exercise, and nearly half of the athletes believed that supplements improved their performance. In addition, it was revealed that athletes who take supplements have healthier feeding behaviors than those who do not. Thus, these findings confirm the necessity of informing fitness athletes about using supplements.
Effects of improved on-farm crop storage on DNA methylation of mothers and their infants: evidence from a randomized controlled trial in Kenya
Authors: Eichenauer Heike , Fischer Susanne , Gardini Elena , Onsongo Simon , Ehlert Ulrike
Published: July 2024

Background

Stress during pregnancy can lead to adverse maternal and infant health outcomes through epigenetic changes in the hypothalamic–pituitary–adrenal axis. Among farmers in low-income countries, one important stressor is food insecurity, which can be reduced using hermetic storage bags. This study aimed to determine, for the first time, whether a hermetic storage bag intervention during pregnancy positively affects maternal and infant DNA methylation of the hypothalamic–pituitary–adrenal axis-related genes FKBP5 and NR3C1. We further analyzed whether anthropometrics, stress, and mental health were associated with DNA methylation.

Methods

This study was part of a larger matched-pair randomized controlled trial focusing on the impact of improved on-farm storage on food security, poverty, and net income of smallholder farming households. A total of N = 149 mothers were recruited by telephone and invited to attend a study appointment at health facilities in Kakamega County, Western Kenya, with their infants in April or May 2021. During the appointment, anthropometric measurements were taken, questionnaires on stress and mental health were administered, and saliva samples were collected. Logistic and multiple linear regression were used to examine the effect of the intervention and related measures on DNA methylation.

Results

Mothers in the intervention group showed higher mean NR3C1 methylation levels than those in the control group, corrected for multiple testing. Maternal postpartum body mass index was positively associated with infant NR3C1 CpG3 DNA methylation. The more stressful life events a mother had experienced in the previous 12 months (including during pregnancy), the lower her FKBP5 CpG3 methylation levels.

Conclusions

Food insecurity and stressful life events during pregnancy seem to exert significant effects on maternal DNA methylation. While these stressors did not appear to impact infant DNA methylation in the present study, maternal postpartum body mass index was significantly related to infant methylation. These findings suggest that while infants may be protected from excessive maternal glucocorticoids by placental barrier activity, maternal metabolic status is still reflected in their epigenetic make-up.

Trial registration This study was part of a larger matched-pair randomized controlled trial on the impact of improved on-farm crop storage on welfare, nutrition, and human health. Registration can be found in the American Economic Association (AEA) RCT Registry, RCT ID: AEARCTR-0005845.
Antiplatelet therapy to prevent ischemic events in giant cell arteritis: protocol for a systematic review and meta-analysis
Authors: Makhzoum Jean-Paul , Baati Youssef , Tanase Octavian , Mendel Arielle , Pagnoux Christian , Ross Carolyn
Published: July 2024

Background

Giant cell arteritis (GCA) is the most common systemic vasculitis in adults. Presenting features include new-onset headaches, constitutional symptoms, jaw claudication, polymyalgia rheumatica, and visual symptoms. Arterial inflammation with subsequent stenosis and occlusion may cause tissue ischemia, leading to blindness, strokes, and myocardial infarction. Oral antiplatelet therapy has been hypothesized to reduce GCA-related ischemic events. However, previous studies have demonstrated conflicting results regarding the efficacy of antiplatelet agents in GCA. The objective of this systematic review is to assess the safety and efficacy of antiplatelet therapy for the prevention of these events in adults with giant cell arteritis.

Methods

In this systematic review, we will include randomized controlled trials (RTCs), quasi-randomized trials, non-randomized intervention studies, cohort studies, and case–control studies on patients with new-onset or relapsing GCA. The intervention of interest will be pre-existing use or initiation of an oral antiplatelet medication (aspirin, clopidogrel, prasugrel, or ticagrelor) at GCA onset or relapse. The comparator of interest will be the absence of antiplatelet therapy. Endpoints will be evaluated after 6 and 12 months of follow-up. The primary outcome will be GCA-related ischemic events, including permanent blindness, stroke, myocardial infarction, and ischemic event-related deaths. Adverse events such as major bleeding and death caused by a bleeding event will be assessed.

Discussion

GCA-related ischemic events are catastrophic, sudden, often irreversible, and lead to significant morbidity. Antiplatelet agents are affordable, accessible, and could be effective for the prevention of these events. Nevertheless, the potential benefits of platelet aggregation inhibition must be weighed against their associated risk of bleeding. Assessing the efficacy and safety of antiplatelet therapy in GCA is therefore clinically important.

Systematic review registration

Our systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO, registration number CRD42023441574.
Real-time scheduling of power grid digital twin tasks in cloud via deep reinforcement learning
Authors: Qi Daokun , Xi Xiaojuan , Tang Yake , Zheng Yuesong , Guo Zhengwei
Published: July 2024

As energy demand continues to grow, it is crucial to integrate advanced technologies into power grids for better reliability and efficiency. Digital Twin (DT) technology plays a key role in this by using data to monitor and predict real-time operations, significantly enhancing system efficiency. However, as the power grid expands and digitization accelerates, the data generated by the grid and the DT system grows exponentially. Effectively handling this massive data is crucial for leveraging DT technology. Traditional local computing faces challenges such as limited hardware resources and slow processing speeds. A viable solution is to offload tasks to the cloud, utilizing its powerful computational capabilities to support the stable operation of the power grid. To address the need, we propose GD-DRL, a task scheduling method based on Deep Reinforcement Learning (DRL). GD-DRL considers the characteristics of computational tasks from the power grid and DT system and uses a DRL agent to schedule tasks in real-time across different computing nodes, optimizing for processing time and cost. We evaluate our method against several established real-time scheduling techniques, including Deep Q-Network (DQN). Our experimental results show that the GD-DRL method outperforms existing strategies by reducing response time, lowering costs, and increasing success rates.
Sublingual sufentanil for patient-controlled analgesia during labor induction for pregnancy termination: an effective and well-tolerated approach
Authors: Fierro Giulia , Milan Barbara , Buelli Elena , Bugada Dario , Casarotta Erika , Rizzo Francesco , Ongaro Laura , Gritti Paolo , Previdi Fabio , Lorini Ferdinando Luca
Published: July 2024

Background

Effective pain management during labor induction for pregnancy termination is essential. However, to date, no effective treatment has been identified. The primary aim of this study was to measure the analgesic efficacy of a sufentanil sublingual tablet system during pregnancy termination and patient satisfaction by comparing nulliparous and multiparous women. The secondary aims were to characterize the safety profile by reporting any side effects or adverse events and to determine the need for rescue therapy.

Methods

We conducted an observational, retrospective, single-center study involving 48 women. The data retrieved for analysis included the total and hourly doses of sublingual sufentanil, evaluations of pain management satisfaction using a 5-point rating scale (ranging from 1, indicating “not satisfied” to 5, denoting “completely satisfied”), occurrence of side effects and adverse events, and the rate of rescue analgesic use. Categorical and numerical variables were compared between the two groups, and a correlation analysis was performed.

Results

The median total dose of sufentanil required was 60 mcg. Nulliparous women required a higher dose of sufentanil compared with multiparous women (105 mcg vs. 45 mcg; P = 0.01). Additionally, they underwent a longer labor, indirectly measured by the time of device usage (625 min vs. 165 min; P = 0.05). Regarding satisfaction, 40 patients (83.4%) were satisfied or completely satisfied, whereas only 8 patients (16.6%) reported dissatisfaction. Multiparous women exhibited higher satisfaction levels than did nulliparous women (P = 0.03). No adverse events were reported, and the most common side effects were nausea and vomiting (31.2%). Four patients (12%) required acetaminophen due to insufficient analgesia, with only one patient necessitating a switch to intravenous morphine.

Conclusions

Sublingual sufentanil was effective in both nulliparous and multiparous women with minimal side effects. Therefore, sublingual sufentanil can be considered a valid strategy for analgesia during labor induction for pregnancy termination.
Association between clinical and disease characteristics and detectable or undetectable baseline ctDNA in patients with metastatic uveal melanoma.
Authors: Nathan Paul D. , Collins Laura , Carvajal Richard D. , Thiyagarajah Piruntha , Sullivan Ryan J. , Sacco Joseph J
Published: July 2024

9537

Background: Tebentafusp, a bispecific soluble TCR specific for a gp100 peptide, is licensed for the treatment of metastatic uveal melanoma (mUM) in HLA-A*02:01+ individuals. 82% of patients (pts) with mUM in the IMCgp100-102 (previously treated; 2L+) and 61% in IMCgp100-202 (frontline; 1L) studies, respectively, had detectable baseline ctDNA. There is a strong relationship between decrease in ctDNA by 9 weeks and overall survival (OS) [Carvajal 2022; Hassel & Piperno-Neumann 2023]. Patients with undetectable baseline ctDNA had improved survival despite having macroscopic disease. In this study, we report the characteristics of baseline ctDNA undetectable vs detectable disease. Methods: Disease characteristics of 202 1L (Study 202) and 117 2L+ (Study 102) pts who had baseline undetectable or detectable ctDNA (unDNA vs detDNA) were compared in a post-hoc unplanned analysis. ctDNA detection was analysed at baseline and up to week 9 on tebentafusp using targeted mPCR-NGS assay for mutations in 15 genes including GNAQ, GNA11, SF3B1, CYSLTR2, PLCB4 and EIF1AX. Largest lesion size groups (≤ 3 cm, 3-8 cm, > 8 cm) were defined by American Joint Committee on Cancer 7th Ed. Presence of oncogenic mutations in GNAQ, GNA11, SF3B1 and BAP1 were assessed by WES on metastatic tissue biopsies. Results: Baseline ctDNA levels increased in association with size of largest lesion regardless of number of prior therapies. However, there was an association between disease burden (defined by largest lesion size) and unDNA vs detDNA in both studies, with all pts with largest liver lesion > 8 cm having detDNA. In Study 202, % of the population with unDNA vs detDNA was 50% vs 50% for ≤ 3cm and 27% vs 73% for 3.1-8 cm. While OS was similar for unDNA & detDNA in pts with ≤ 3cm lesions, OS was longer for pts with unDNA vs detDNA who had baseline tumor size 3.1-8 cm in both studies (Table). Within this 3.1-8 cm group, pts with unDNA tended to have lower LDH, AST, and ALP. Initial analysis showed no difference in the frequency of GNAQ, GNA11, SF3B1 or BAP1 mutations between unDNA and detDNA groups. Further data on somatic mutation defined groups and RNAseq gene expression in unDNA and detDNA groups will be presented. Conclusions: Patients with unDNA were more likely to have smaller disease burden than those with detDNA; however, many pts with unDNA had a significant burden of metastatic disease. Baseline unDNA was associated with improved OS outcome vs detDNA in pts with 3.1-8 cm baseline metastatic deposits, but not in pts with ≤ 3cm disease. No association was seen between oncogenic background of GNAQ/GNA11/SF3B1/BAP1 and unDNA vs detDNA. Clinical trial information: NCT02570308 ; NCT03070392 . [Table: see text]
Outcomes of personalized therapy guided by Exacta encyclopedic tumor analysis for women with broadly refractory advanced breast cancer.
Authors: Crook Tim , Limaye Sewanti , Ranade Anantbhushan , Bhatt Amit Dilip , Apurwa Sachin , Patil Darshana , Datar Rajan , Kurzrock Razelle
Published: July 2024

e13124

Background: Following the failure of three lines of systemic treatments in breast cancers, Standard of Care guidelines typically recommend palliative care or participation in clinical trials for such patients. Breast cancer remains a global health threat, impacting lives worldwide. For refractory patients, the outlook is grim, with limited treatment options post multiple failures. Dismal outcomes underscore the urgency for innovative approaches, as traditional interventions often fall short. Methods: The Resilient trial was a Phase-II, single-arm, open-label clinical trial. Its primary objective was to assess the effectiveness of Exacta ETA-guided treatments across a spectrum of solid organ cancers in advanced refractory cancer patients. Exacta Encyclopedic Tumor Analysis (ETA) comprising the interrogation of gene alterations, gene expression, immunohistochemistry (IHC), and in vitro chemoresistance profiling (CRP) of viable tumor cells was performed on freshly obtained tumor tissue from 21 breast cancer patients with broadly refractory advanced breast cancers who had failed multiple lines of treatment. Six (29%) patients had metastasis to the brain, 11 (52%) patients had metastasis to the liver, 9 (43%) patients had metastasis to the lungs, and 15 (71%) patients had skeletal metastasis. The findings obtained through Exacta ETA were integrated to formulate patient-specific therapy recommendations. Personalized treatment plans were devised, and organ- and label-agnostic treatment regimens were administered to each patient. Patients were monitored to ascertain Overall Survival (OS). Results: Median overall survival (OS) was not reached at the time of analysis. By considering the OS values censored at the interim (most recent follow-up), the median OS in the entire cohort (n = 21) was 11.5 months (95% CI 4.5 to 16.9). The median OS was 11.4 months (95% CI 4.0 to 15.1) among patients with brain metastases, 14.5 months (95% CI 2.6 to 22.8) among patients with liver metastases, 11.9 months (95% CI 3.7 to 22.3) among patients with pulmonary metastases and 11.4 months (95% CI 3.7 to 22.3) among patients with skeletal metastases, respectively. No grade IV adverse events or treatment-related deaths were reported in the cohort. Conclusions: Exacta Encyclopedic Tumor Analysis (ETA) guided treatments provide a viable and meaningful treatment option for patients with advanced refractory breast cancers with metastatic deposits. The observed high OS in this heavily pretreated population underscores the value of multi-analyte guided of Exacta ETA as a valuable approach to managing these challenging clinical cases. Clinical trial information: CTRI/2018/02/011808.
Clinical validation of Northstar response: A novel methylated ctDNA therapy response monitoring assay in patients with advanced gastrointestinal cancers.
Authors: Sahin Ilyas , Kahramangil Doga , Kim George P. , Rogers Sherise C. , Ramnaraign Brian Hemendra , Manda Pravalika , Varga Matthew Gordon , Palmer Gary A. , Ye Patrick Peiyong , George Thomas J.
Published: July 2024

e16000

Background: Circulating tumor DNA (ctDNA) offers a non-invasive method to comprehensively assess tumors. While most assays for therapy response monitoring rely on variant allele frequencies, methylated ctDNA has shown promise. However, accuracy has been limited by quantification precision. The CLIA-approved Northstar Response assay quantifies over 550 hyper-methylated loci and has demonstrated a 10-fold increase in detection signal over tissue-informed assays. Methods: We present an interim analysis from an ongoing prospective, observational study designed to assess the clinical validity of Northstar Response as a tool to monitor therapeutic response without prior tumor tissue. Our study aims to include 100 advanced GI cancer patients undergoing systemic therapies for advanced disease. Serial ctDNA measurements are collected at baseline, approximately every 30 days post-treatment initiation, and with imaging assessments. The primary endpoint is concordance between ctDNA and RECISTv1.1 criteria for disease response until progression or death. Results: Baseline ctDNA characteristics were examined from 44 patients, with 23 undergoing at least two longitudinal blood collections and subsequent imaging. The median age in this cohort was 65.5 years, with a male predominance (70.5%) and a majority identifying as White (79.5%). Cancers included esophageal (18.2%), hepatocellular (29.5%), biliary (15.9%) and colorectal (15.9%), among others. A majority (59.1%) had both primary and metastatic lesions. Baseline methylation scores ranged from 280 in biliary cancers to 100,000 in colorectal cancers. Those on second-line treatments had lower scores than first or third-line therapies. Methylation scores decreased in patients responding to treatment, indicating that these scores have the potential to serve as indicators of therapeutic efficacy. Conclusions: Baseline methylation scores differ across GI tumor types, disease burdens, and treatment lines, reflecting the complexity of using methylation as a biomarker. Northstar Response has shown initial promise in monitoring therapy response in GI cancers. More mature data, which will further elucidate the assay's clinical utility, will be presented at the meeting.
Trends and disparities in the incidence and mortality of stomach cancer in the United States.
Authors: Ajibawo Temitope
Published: July 2024

e16102

Background: Stomach cancer is the fifth most common cancer worldwide and has one of the lowest survival rates across all malignancies. There is a constant need to define current stomach cancer incidence and incidence-based mortality (IBM) rates among different population groups for improved clinical practice. We aimed to investigate the trends of stomach cancer incidence and IBM by population characteristics of age groups, gender and ethnic groups. Methods: Data obtained from the National Cancer Institute’s Surveillance, Epidemiology, and End results (SEER) Registry 12 were obtained to determine the incidence and IBM rate of stomach incidence from 1992 to 2020. Joinpoint Regression Analysis program was used to calculate the annual percent change (APC) for trend analysis. Results: A total of 82,810 stomach cancer patients were identified from the dataset. Most of the patients were males; N = 49,909(60.27%) and Non-Hispanic Whites, N = 40,894 (49.38%). The overall incidence rate was 8.00 (95% Confidence Interval [CI]: 7.95 to 8.06) and the overall IBM rate was 6.44 (95%CI: 6.39 to 6.49). The incidence rate of stomach cancer decreased significantly by 1.28 % per year from 1992 to 2020; however the degree of decline from 1992 to 2017, APC (-1.18, 95% CI: -1.27 to -1.04, p < .001) was lower compared to between 2017 and 2020, APC (-3.42, 95% CI: -6.08 to -1.69, p = 0.01). Conversely, IBM rate increased significantly from 1992 to 1994, APC (36.59, 95% CI: 22.51 to 52.29, p < .001) followed by a significant decrease from 1994 to 2020, APC (-1.29, 95%CI: -1.43 to -1.15, p < .001).Incidence rates reduced significantly from 1992 to 2020 for all gender, ethnic and age groups except among the Non-Hispanic Asian Indian or Alaska Native (NHAIAN) population with APC (-0.67, 95 CI% -1.93 to 0.61, p = 0.29) and < 60 years age group with APC (0.03, 95 CI % : 0.18 to 0.25, p = 0.76). Significant decline in IBM rate was observed from 2000 to 2020 across all gender, ethnicities and age groups except among the NHAIAN, APC (-0.21, 95 CI%: -1.26 to 0.84, p = 0.68) and the < 60 years age group, APC (0.16, 95 CI%: -0.33 to -0.65, p = 0.52). Conclusions: Stomach cancer incidence and IBM rates have decreased significantly over the last 20 years except in NHAIAN and < 60 years age populations. These findings suggest the need for further research focused efforts in these potentially high-risk groups.