bluuebunny/crossref_metadata_2025_split huggingface dataset:
Generalization of the sci-L3 method to achieve high-throughput linear amplification for replication template strand sequencing, genome conformation capture, and the joint profiling of RNA and chromatin accessibility
Authors: Chovanec Peter , Yin Yi 
Published: February 2025

Abstract
Single-cell combinatorial indexing (sci) methods have addressed major limitations of throughput and cost for many single-cell modalities. With the incorporation of linear amplification and three-level barcoding in our suite of methods called sci-L3, we further addressed the limitations of uniformity in single-cell genome amplification. Here, we build on the generalizability of sci-L3 by extending it to template strand sequencing (sci-L3-Strand-seq), genome conformation capture (sci-L3-Hi-C), and the joint profiling of RNA and chromatin accessibility (sci-L3-RNA/ATAC). We demonstrate the ease of adapting sci-L3 to these new modalities by only requiring a single-step modification of the original protocol. As a proof of principle, we show our ability to detect sister chromatid exchanges, genome compartmentalization, and cell state-specific features in thousands of single cells. We anticipate sci-L3 to be compatible with additional modalities, including DNA methylation (sci-MET) and chromatin-associated factors (CUT&Tag), and ultimately enable a multi-omics readout of them.
Phosphorylated BLM peptide acts as an agonist for DNA damage response
Authors: Agrawal Ritu , Agarwal Himanshi , Mukherjee Chetana , Chakraborty Baishali , Sharma Vandana , Tripathi Vivek , Kumar Nitin , Priya Swati , Gupta Nidhi , Jhingan Gagan Deep , Bajaj Avinash , Sengupta Sagar 
Published: February 2025

Abstract
Upon exposure to ionizing irradiation, the MRE11–RAD50–NBS1 complex potentiates the recruitment of ATM (ataxia-telangiectasia mutated) kinase to the double-strand breaks. We show that the lack of BLM causes a decrease in the autophosphorylation of ATM in mice mammary glands, which have lost one or both copies of BLM. In isogenic human cells, the DNA damage response (DDR) pathway was dampened in the absence of BLM, which negatively affected the recruitment of DDR factors onto the chromatin, thereby indicating a direct role of BLM in augmenting DDR. Mechanistically, this was due to the BLM-dependent dissociation of inactive ATM dimers into active monomers. Fragmentation analysis of BLM followed by kinase assays revealed a 20-mer BLM peptide (91–110 aa), sufficient to enhance ATM-dependent p53 phosphorylation. ATM-mediated phosphorylation of BLM at Thr99 within BLM (91–110) peptide enhanced ATM kinase activity due to its interaction with NBS1 and causing ATM monomerization. Delivery of phosphomimetic T99E counterpart of BLM (91–110 aa) peptide led to ATM activation followed by restoration of the DDR even in the absence of ionizing irradiation (both in cells and in BLM knockout mice), indicating its role as a DDR agonist, which can be potentially used to prevent the initiation of neoplastic transformation.
Rescuing DNMT1 fails to fully reverse the molecular and functional repercussions of its loss in mouse embryonic stem cells
Authors: Elder Elizabeth , Lemieux Anthony , Legault Lisa-Marie , Caron Maxime , Bertrand-Lehouillier Virginie , Dupas Thomas , Raynal Noël J-M , Bourque Guillaume , Sinnett Daniel , Gévry Nicolas , McGraw Serge 
Published: February 2025

Abstract
Epigenetic mechanisms are crucial for developmental programming and can be disrupted by environmental stressors, increasing susceptibility to disease. This has sparked interest in therapies for restoring epigenetic balance, but it remains uncertain whether disordered epigenetic mechanisms can be fully corrected. Disruption of DNA methyltransferase 1 (DNMT1), responsible for DNA methylation maintenance, has particularly devastating biological consequences. Therefore, here we explored if rescuing DNMT1 activity is sufficient to reverse the effects of its loss utilizing mouse embryonic stem cells. However, only partial reversal could be achieved. Extensive changes in DNA methylation, histone modifications, and gene expression were detected, along with transposable element derepression and genomic instability. Reduction of cellular size, complexity, and proliferation rate were observed, as well as lasting effects in germ layer lineages and embryoid bodies. Interestingly, by analyzing the impact on imprinted regions, we uncovered 20 regions exhibiting imprinted-like signatures. Notably, while many permanent effects persisted throughout Dnmt1 inactivation and rescue, others arose from the rescue intervention. Lastly, rescuing DNMT1 after differentiation initiation worsened outcomes, reinforcing the need for early intervention. Our findings highlight the far-reaching functions of DNMT1 and provide valuable perspectives on the repercussions of epigenetic perturbations during early development and the challenges of rescue interventions.
CSF protein biomarkers are associated with response to multi-agent intraventricular chemotherapy in patients with CNS lymphoma
Authors: Aastha Aastha , Wilding Hannah , Mikolajewicz Nicholas , Khan Shahbaz , Ignatchenko Vladimir , De Macedo Filho Leonardo Jose Monteiro , Bhanja Debarati , Remite-Berthet Gabriela , Heebner Madison , Glantz Michael , Mansouri Alireza , Kislinger Thomas 
Published: February 2025

Abstract

Background
Central nervous system lymphoma (CNSL), is a rare subtype of non-Hodgkin lymphoma, primarily affecting the brain and spinal cord. Most therapeutic systemic agents have limited penetration of the blood-brain and blood-cerebrospinal fluid barrier, with the latter potentially promoting a treatment “sanctuary” for cancer cells. Evaluation of occult disease, particularly in the cerebrospinal fluid (CSF), is challenging. In limited clinical experience the addition of multi-agent intraventricular chemotherapy (MAIVC), delivered through intracranially-implanted CSF reservoirs, to systemic therapy has demonstrated encouraging outcomes, enhancing both progression-free survival and overall survival. However, given the potential morbidity associated with MAIVC, identification of minimally-invasive biomarkers for guiding patient selection and management are necessary. Leveraging the longitudinal, large volume of CSF, the objective of this study was to identify CSF-based proteomic biomarkers that can serve as reliable indicators of CSF clearance in response to MAIVC and CNSL treatment outcome.

Methods
115 CSF samples from 59 CNSL patients receiving MAIVC were profiled using a high-throughput protocol coupled with mass-spectrometry that only requires 30 μL of CSF.

Results
More than 2000 unique proteins were detected using shotgun proteomics. CSF proteomics revealed key proteins (SGCE, LCP1, AGRN, OLFML3, HRSP12) distinguishing early from never responders to MAIVC, with AUROC 0.86 (95% CI: 0.696-1). By integrating tumor volume from brain MRI scans with proteomic data, we identified potential intraventricular tumor burden markers for CNSL management, in particular LCP1.

Conclusions
The study identified CSF-based proteomic biomarkers, particularly LCP1, that can classify MAIVC response and indicate tumor burden in CNSL patients.
Does Adjusting for Causal Intermediate Confounders Resolve the Perinatal Crossover Paradox?
Authors: Loh Wen Wei , Ananth Cande V. 
Published: February 2025

Background:
Mediation analyses of the pre-eclampsia–perinatal outcome association through preterm birth (PTB) have produced paradoxical findings. For example, pre-eclamptic births at preterm gestations show a lower risk of adverse outcomes than normotensive births. These results have been explained by unmeasured baseline confounding between PTB and outcomes, with PTB as the sole mediator. However, other intermediate variables, such as placental abruption, small for gestational age (SGA) births, and chorioamnionitis, are confounders yet are excluded because they occur after pre-eclampsia.

Methods:
Using data from the Consortium on Safe Labor (2002–2008;

), we utilized interventional indirect effects to examine whether adjusting for causal intermediates mitigates confounding bias to resolve the perinatal paradox. We compared two approaches to handle intermediate confounding by abruption, SGA, and chorioamnionitis when PTB is the focal mediator: as exposure-induced confounders or as multiple mediators. We developed bias formulas to assess unmeasured confounding for interventional effects.

Results:
When PTB was the sole mediator, the estimated protective direct effect of pre-eclampsia (risk ratio = 0.60; 95% confidence interval = 0.52, 0.71) was in line with previous paradoxical findings. The estimated protective effect persisted even after adjusting for intermediate confounders. Sensitivity analyses suggested an unmeasured confounder must strongly influence the outcome to resolve the paradox.

Conclusion:
Adjusting for causal intermediates such as abruption, SGA, and chorioamnionitis is inadequate to eliminate unmeasured PTB–perinatal mortality confounding. The paradox of pre-eclampsia’s protective direct effect on mortality remains unresolved. Sensitivity analyses to unmeasured confounding are effective in bolstering conclusions from causal mediation analyses and should be more widely applied.
Pupillary dilation to monitor nociception in awake volunteers
Authors: Malewicz-Oeck Nathalie M. , Skorupka Nic , Bartholmes Felix , Dombrowski Adeline , Ebel Melanie , Zahn Peter K. , Meyer-Frießem Christine H. 
Published: February 2025

BACKGROUND
Pupillary reflex dilation (PRD) quantifies nociception in anaesthetised patients, enabling tailored opioid administration, which in turn reduces catecholamine levels and postoperative pain intensity. However, its utility in objectively assessing pain in awake individuals remains challenging.

OBJECTIVE
To investigate whether PRD can differentiate between painful and nonpainful stimuli in awake volunteers.

DESIGN
This was a randomised, placebo-controlled, stimuli-randomised study conducted after ethical approval and registration (DRKS00024791).

SETTING
This single-centre study was performed at BG University Hospital Bergmannsheil Bochum, Germany, between November 2021 and January 2022.

VOLUNTEERS
Thirty healthy volunteers (25 ± 2 years, 50% male) were included in the study.

INTERVENTIONS
After a rest, the following were stimuli applied to one ventral forearm: an unannounced electric pain stimulus (UPS) and a randomised sequence of either an announced painful stimulus (APS), a placebo or a nonpainful stimulus (NPS).

MAIN OUTCOME MEASURES
Pupil dilatation was measured as PRD (%) for 60 s during the experimental condition “rest”, and during and after each stimulus application using an AlgiScan device. The participants rated stimulus pain intensity via a numeric rating scale (NRS: 0 = no pain, 10 = most intense pain imaginable). Statistics: Paired t-test, rmANOVA, Spearman's correlation and receiver operating characteristics (ROC), P < 0.05.

RESULTS
The subjective pain intensity ratings were higher after APS (6.0 ± 1.9) than after UPS (5.5 ± 1.7, P = 0.007), placebo (0.0 ± 0.0, P = 0.027) and NPS (0.0 ± 0.0, P = 0.001). Similarly, objective pupillary reaction to the stimuli measured using PRD was higher for APS: 13 (97.6% CI, 10.0 to 19.0)% vs. NPS 13 (97.6% CI, 7.0 to 20.0), P = 0.024). UPS elicited the highest PRD of 25 (95.7% CI, 18.0 to 30.0)% vs. rest, P < 0.001; significantly greater than placebo at 13.5 (96.4% CI, 10.0 to 22.0)%, P < 0.001); and NPS at 13 (97.6% CI, 7.0 to 20.0)%, P < 0.0001). However, no significant differences in PRD were observed between APS and UPS despite their electrical similarity. PRD correlated with pain intensity (r = 0.35, P < 0.0001).

CONCLUSIONS
In awake volunteers, PRD differentiates between painful and nonpainful stimuli and correlates with pain intensity. Noninvasive PRD measurement may be suitable for nociception monitoring in awake individuals.

TRIAL REGISTRATION
Prospectively DRKS00024791, March 2021.
Socioeconomic marginalization is associated with delayed medical consultation among endometrial cancer patients presenting with postmenopausal bleeding
Authors: Abu Zhaya Aied , Helpman Limor , Korach Jacob , Yaniv Assaf , Blecher Anna , Rozanblat Orgad , Yagel Itai , Kadan Yfat 
Published: February 2025

Abstract

Objective
The key presenting symptom of endometrial cancer is abnormal uterine bleeding, most commonly postmenopausal bleeding (PMB), which facilitates early-stage diagnosis. This study aimed to investigate factors influencing delayed medical consultation for PMB, and particularly its association with social determinants.

Methods
This is a retrospective study that included endometrial cancer patients receiving care in a gynecologic oncology department of a tertiary medical center who presented with PMB. Demographic and oncologic data was collected from the electronic medical charts. Israeli bureau of statistics data was used to assess community socioeconomic index, based on address. Women seeking consultation more than 1 month after experiencing PMB were compared to those seeking earlier care.

Results
Two hundred ninety-five women were included in the study. One hundred seventy-three sought care after less than 1 month of PMB (early presenters) and 122 sought care after more prolonged PMB (late presenters). Late presenters were more likely to be socioeconomically marginalized (odds ratio [OR], 1.8; P = 0.018), higher body mass index (OR, 1.040; P = 0.022), and greater parity (OR, 1.170; P = 0.032). Socioeconomic marginalized patients experienced a 7-day longer delay from diagnosis to surgery compared to their privileged counterparts (59 vs 52 d, P = 0.022).

Conclusions
Among women with endometrial cancer, longer duration of PMB before first seeking medical consultation is associated with socioeconomic marginalization. This highlights the need for targeted interventions to minimize delays in diagnosis and treatment initiation among patients from marginalized communities.
Interpersonal dyadic influences on transitions between pain states: a narrative review and synthesis
Authors: Birkinshaw Hollie , de C Williams Amanda C , Friedrich Claire , Lee Charlotte , Keogh Edmund , Eccleston Christopher , Pincus Tamar 
Published: February 2025

Abstract
Pain is not experienced in isolation; it is affected by and affects other people. Interactions between parents and partners and people living with pain affect beliefs, emotions and behaviours, and pain progress and change. We searched systematically for longitudinal studies of associations between specific familial, dyadic, interpersonal factors and quantitative pain transitions. We coded studies for risk of bias. For the narrative synthesis, we grouped findings by dyads—parents and children, and people with pain and their partners (usually spouses), and then by the psychosocial mechanism/s. We described certainty of evidence for each pain transition and each mechanism. Patient and public contributors were involved throughout. Of 52 studies, 38 were of parents and children (27,814 dyads) and 14 of partners (4904 dyads). Three groups of predictive factors were identified for parent and child studies: parent mental health, parent cognitions, and parent behaviours. Parental anxiety (but not depression) predicted children's onset of pain and worsening; the evidence was of moderate certainty and almost exclusively involved mothers. Evidence that some parental behaviours, such as protective behaviours, were associated with worse child pain was of very low certainty. The evidence for partners was of poor quality, precluding synthesis. The review highlights that most interpersonal pain research fails to capture the complex dynamics of longstanding relationships and highlights the difficulty of doing so using simple models.
Liver resection versus radiofrequency ablation for solitary small hepatocellular carcinoma measuring≤3cm: a systematic review and meta-analysis
Authors: Yang Ming , Li Guangjun , Chen Kunlin , Wu Youwei , Sun Ting , Wang Wentao 
Published: February 2025

Background:
Controversy remains regarding liver resection (LR) and radiofrequency ablation (RFA) for patients with single hepatocellular carcinomas (HCCs) measuring 3 cm or less. The purpose of our study was to compare the prognosis between LR and RFA in patients with solitary HCCs ≤3 cm.

Methods:
The meta-analysis followed the PRISMA guidelines and the Cochrane Handbook. All RCTs and cohort studies that compared LR versus RFA in patients with solitary HCCs≤3 cm were comprehensively searched in the PubMed, Cochrane Library, Embase, and Web of Science databases up to 30 January 2024. The primary endpoints were overall survival (OS), recurrence-free survival (RFS), and disease-free survival (DFS).

Results:
A total of 6356 patients with solitary HCCs≤3 cm and 5829 patients with solitary HCCs≤2 cm from 39 included studies were analyzed (LR = 5759, RFA = 6426). The present meta-analysis of two RCTs showed no statistically significant difference in OS between LR and RFA. However, the meta-analysis of cohort studies revealed that, compared with RFA, LR conferred a superior OS advantage (HR = 0.80, 95% CI: 0.68–0.93, P = 0.005). There was a significant improvement in the DFS rate with LR over RFA (HR = 0.63, 95% CI: 0.49–0.81) and in the RFS rate (HR = 0.65, 95% CI: 0.55–0.76). Compared with RFA, LR resulted in better OS (HR = 0.73, 95% CI: 0.54–0.97), DFS (HR = 0.74, 95% CI: 0.67–0.82) and RFS (HR = 0.71, 95% CI: 0.57–0.90) in patients with a solitary HCC lesion ≤2 cm.

Conclusions:
Evidence from cohort studies suggested that in patients with a solitary HCC lesion ≤ 3 cm, LR is preferable to RFA. Additional RCTs are needed to confirm the validity of this evidence.
The July Effect on Mortality, Hospital Length of Stay, and Time to Colonoscopy Among Patients Presenting to Teaching Hospitals With LGIB in the United States
Authors: Annor Eugene , Amadi Chima , Atarere Joseph , Ubah Nneoma , Awolumate Oluwatayo J. , Adenusi Adedeji , Nabeta Geraldine Nabiryo , Downs Darrell , Abegunde Ayokunle T. 
Published: February 2025

Background and Aim:
The “July effect” refers to increased morbidity and mortality observed when new medical trainees start at teaching hospitals in July. This phenomenon has been noted in various conditions but has not been extensively studied in lower gastrointestinal bleeding (LGIB). LGIB accounts for 20% to 30% of major gastrointestinal bleeding admissions, with a mortality rate of 2% to 4%. This study aimed to assess the impact of the “July effect” on clinical outcomes for patients with LGIB admitted to teaching hospitals in the United States from 2016 to 2020.

Methods:
This retrospective cohort study analyzed data from the Nationwide Inpatient Sample (2016 to 2020). The primary outcomes were inpatient mortality, hospital length of stay (LOS), and delays in early colonoscopy, defined as more than 24 hours from admission. The key variable was the month of admission, categorized into pre-July (May and June) and July effect (July and August) periods. Survey-weighted multivariable logistic and Poisson regression models were used to evaluate the month of admission’s impact on outcomes.

Results:
The study included 27,425 admissions, with 13,746 (50.1%) in May and June and 13,679 (49.9%) in July and August. Less than two-thirds (59.2%) of LGIB admissions received a colonoscopy during hospitalization. Among the 15,708 patients who underwent colonoscopy within 7 days of admission, 40.8% had an early colonoscopy (within 24 h). The overall mean hospital LOS was 4.4 days, with an in-hospital mortality rate of 1%. There was no significant “July effect” on delays in early colonoscopy [adjusted odds ratio (aOR) 1.06, 95% CI (0.99, 1.13)], hospital LOS [adjusted incidence rate ratio (aIRR) 1.02, 95% CI (1.00, 1.04)], or in-hospital mortality [aOR 1.17, 95% CI (0.91, 1.50)].

Conclusion:
The study found no evidence of a “July effect” on in-hospital mortality, LOS, or delays in early colonoscopy for LGIB patients. Despite the influx of new trainees in July, patient care for LGIB in teaching hospitals seems consistent, indicating that current protocols and supervision effectively mitigate risks. Further research is needed to explore other factors influencing LGIB outcomes and overall patient care during this period.
Small bowel ultrasound: friend or foe?
Authors: Wild James , Nandi Nicoletta , Chew Thean Soon , Rea Benjamin , Sidhu Reena 
Published: February 2025

Purpose of review
Crohn's disease (CD), requires accurate diagnosis and regular monitoring to manage disease activity, prevent complications, and improve outcomes. Intestinal ultrasound (IUS) has emerged as a noninvasive, real-time imaging modality, offering a valuable alternative to traditional diagnostic techniques such as magnetic resonance enterography (MRE), endoscopy and capsule endoscopy (CE). This review examines recent advances in IUS for the diagnosis and monitoring of small bowel CD, with a focus on its applications, benefits, and limitations.

Recent findings
Recent studies have demonstrated that IUS provides high sensitivity and specificity in detecting key markers of disease activity, including bowel wall thickness (BWT), bowel wall flow (BWF), and bowel wall stratification (BWS). Advances in IUS techniques, such as elastography and contrast-enhanced ultrasound (CEUS), have expanded its diagnostic and prognostic capabilities, potentially enabling differentiation between inflammation and fibrosis. However, challenges remain, including operator dependency, variability in scoring systems, and reduced sensitivity for superficial mucosal abnormalities. Efforts to standardize parameters and improve training have shown promise in addressing these limitations.

Summary
IUS is a critical complementary tool for assessing disease activity, transmural healing, and postoperative recurrence in small bowel CD. Its noninvasiveness, cost-effectiveness, and real time assessment make it well suited for routine clinical use. Nonetheless, further multicentre studies are needed to validate scoring systems, optimize integration with other modalities, and improve consistency across clinical settings. IUS holds significant potential for advancing personalized care in small bowel CD, though ongoing research is required to refine its applications and maximize its clinical utility.
Contemporary management of portal vein thromboses in patients with and without cirrhosis
Authors: Shenoy Abhishek , Davis Jessica P.E. 
Published: February 2025

Purpose of review
Portal vein thromboses (PVT) is a common clotting disorder that can be seen in patients with and without cirrhosis. There are no current clinical guidelines on management of portal vein thromboses in these two distinct populations given most studies are retrospective and comprised of heterogenous cohorts.

Recent findings
When evaluating PVT, patients must first be stratified into those with cirrhosis and those without cirrhosis. In addition, a novel nomenclature can help categorize specific PVT types and determine the need and response to anticoagulation. The management of PVT in patients with cirrhosis varies and is primarily dependent on whether the PVT is recent or chronic. In contrast, patients without cirrhosis are almost always anticoagulated to avoid complications of PVT. Direct oral anticoagulants, low-molecular weight heparin, and vitamin-K antagonists have all been used in patients with and without cirrhosis, without clear guidance on optimal treatment duration and surveillance.

Summary
Direct oral anticoagulants are increasingly used for patients with PVT though there is limited data on the safety and efficacy of these medications. The risk/benefit profiles of various anticoagulants must be considered when choosing a therapeutic anticoagulant. There are ongoing studies evaluating outcome measures of different anticoagulants in patients with PVT. Large, multicenter, randomized controlled trials may help elucidate the efficacy of anticoagulants on various outcome measures in PVT, including recanalization, bleeding, and survival.