bluuebunny/crossref_metadata_2025 huggingface dataset:
Screening tools for malignancy in patients with cryptogenic stroke: Systematic review
Authors: Tieck Maria P , Single Constanze , Poli Sven , Kowarik Markus C , Ziemann Ulf , Mengel Annerose , Feil Katharina
Published: February 2025

Up to 20% of patients with cryptogenic ischemic stroke have an occult malignancy at the time of stroke presentation, providing an opportunity for early cancer detection. Despite this significant association, there is currently no consensus in international guidelines on how to systematically screen for malignancy in ischemic stroke patients. This review aims to summarize recent evidence on clinical features and scores, and predictive laboratory tests, that can guide malignancy screening in ischemic stroke patients. Our systemic search included PubMed, MEDLINE and Cochrane databases and yielded a total of 12 studies meeting the inclusion criteria for review. Elevated D-dimer levels and multiple infarcts in different cerebral circulations emerged as key markers. Based on the summarized data, we propose a flowchart for clinical decision-making regarding malignancy screening in patients with ischemic stroke. As the initial steps, we recommend using D-dimers cut-offs and stroke pattern on brain imaging to classify patients according to their risk profile. Based on the identified risk, we recommend a subsequent diagnostic workup addressing the most prevalent cancer types, including gastrointestinal tract, lung adenocarcinoma and gender-related cancer. The clinical implications of early malignancy screening and the need for evidence-based guidelines in cryptogenic stroke are discussed.
Dual versus single antiplatelet therapy in patients with non-cardioembolic acute ischemic stroke and baseline MRI
Authors: De Marchis Gian Marco , Toebak Anna , Dittrich Tolga , Vlachos Dimitrios , Wang Angela , Smith Eric E , Mundl Hardi , Colorado Pablo , Shoamanesh Ashkan , Hart Robert G
Published: February 2025

Introduction:

Dual antiplatelet therapy (DAPT) is superior to single antiplatelet therapy (SAPT) for secondary prevention after minor, non-cardioembolic stroke. We aimed to assess whether DAPT efficacy is modified by large artery atherosclerotic (LAA) etiology, and DAPT safety by stroke size on MRI.

Patients and methods:

Post hoc analysis of the Phase 2 PACIFIC-STROKE randomized clinical trial, which enrolled patients with non-cardioembolic stroke, all with baseline MRI and compared the Factor XIa inhibitor asundexian with placebo on a background of DAPT or SAPT. We compared patients treated with DAPT versus SAPT. The efficacy endpoint was the rate of recurrent ischemic stroke, the safety endpoint was major or clinically relevant non-major bleeding during follow-up.

Results:

1590 patients were included, median NIHSS was 2 (interquartile range [IQR] 1–4), 40% received DAPT. Median follow-up was 11.5 months. The efficacy endpoint occurred in 4.4% and 4.8% in the DAPT group and SAPT group, respectively, with the strongest numerical benefit of DAPT over SAPT among patients with NIHSS ⩽ 3 not treated by intravenous thrombolysis. LAA index stroke etiology did not modify DAPT treatment effect. The safety endpoint occurred more often in the DAPT than in the SAPT group (4.6% vs 2.7%), with the numerically lowest risk among patients with NIHSS ⩽ 3 not treated by intravenous thrombolysis. Stroke size did not modify the effect of DAPT on the safety endpoint.

Discussion and conclusion:

We found no evidence of major treatment effect heterogeneity with DAPT compared with SAPT in patients with and without LAA or by stroke size on MR-DWI.
Genealogy of anger: emotions and violence in Argentinean collective actions
Authors: Lisdero Pedro , Falconier Francisco
Published: February 2025

Anger constitutes an undeniable driving force to comprehend many of the collective actions that have traversed the Argentine reality since the return of democracy. As an expression of a constellation of social emotions that materialize in individuals' experiences, the anger underpinning protests not only questions the disputes over the “correct ways of feeling” in society but also communicates about what it is willing to acknowledge in terms of violence management. Emotion and violence emerge as two privileged lenses to unravel a genealogy of anger that materializes in collective actions. This study aims to approach the aforementioned relationship through a series of concrete postcards of Argentine collective action (since 1983). Without striving for exhaustiveness, a series of postcards are reconstructed from paradigmatic collective actions, enabling the identification of “rhythms” in the connections between anger and violence through the interactions of repertoires and action meanings. The following are analyzed: “escraches” (political actions against individuals accused of crimes against humanity), roadblocks , looting, lynchings and “digital cancellation” actions. Records from virtual ethnographies and in-person interviews engage in dialogue with media records and existing academic literature on the selected paradigmatic cases, all aimed at initially characterizing a genealogy of anger in Argentina.
State, platform capitalism and infrastructural power: Microsoft's data centres in Greece 2.0
Authors: Papaevangelou Charis , Siapera Eugenia
Published: February 2025

This article examines the under-explored role of the state in enabling platform capitalism by analysing Microsoft's infrastructural investment in Greece, as part of the country's post-pandemic ‘National Recovery and Resilience Plan: Greece 2.0’. While much of the critical literature emphasises platform companies’ control over infrastructure and data, we argue that state facilitation is a crucial component of platform capital accumulation. Through a case study of Microsoft's construction of three data centres in the region of Attica, we show how the Greek state actively facilitated this investment, framing it as a driver of modernisation and economic recovery. We base our study on a comprehensive document analysis of official communications, regulatory frameworks and legal documents. This involvement exemplifies how semi-peripheral states like Greece, shaped by neoliberal restructuring and economic dependence, contribute to consolidating the power of tech corporations, often at the expense of local communities and the environment. By integrating theories of state capitalism and techno-colonialism with critical platform scholarship, this article contributes to a deeper understanding of the political economy of platform capitalism, revealing the symbiotic yet exploitative nature of state-tech partnerships and urging a re-centring of the state's role in facilitating corporate dominance over digital infrastructures and global platform capitalism.
Enhancing Pediatric Satisfaction in Healthcare Services: An Integrative Review
Authors: Sharifi Khadijeh , Kalhor Faramarz
Published: February 2025

Background. Facilitating children’s consent and active participation in healthcare decisions not only improves treatment outcomes but also enhances follow-up care. This review examines key factors influencing pediatric patient satisfaction with healthcare services. Methods and materials. An integrated review was conducted, incorporating a thorough literature search, data evaluation, and analysis using Broom’s method. Online databases were systematically searched using predefined keywords for studies published between 2000 and 2024. Two researchers independently applied inclusion/exclusion criteria, reviewed titles and abstracts, and performed content analysis to identify recurring factors. Findings. Out of 146 articles reviewed, key factors influencing pediatric satisfaction included pain relief, communication, environment, and parental stress. These were categorized into five groups: hospitality, treatment outcomes, staff interaction, hospital infrastructure, and parental satisfaction. Conclusion. By considering and prioritizing these factors, healthcare providers can better address the needs of pediatric patients, ultimately improving their treatment experiences and outcomes.
Pediatric Rabies Due to a Feral Cat Bite in the Amazonas Region of Peru: First Rabies Case in a Decade
Authors: Cuela-Martínez Karen Tatiana , Peña-Vásquez Walter , Vásquez-Paz Héctor , Virú-Loza Manuel André
Published: February 2025

We report the first case of human rabies in a child from Amazonas after 10 years without an outbreak. An 8-year-old girl was admitted to the local hospital because of headache, myalgia, diarrhea, fever, and vomiting during the previous 4 days. Meningoencephalitis was suspected, and empiric therapy with ceftriaxone and vancomycin was started. However, in the following 3 days, she also presented progressive lower extremities weakness, behavioral changes, photophobia, irritability, sialorrhea, and hallucinations. Thus, she was transferred to our hospital. Phenytoin, dexamethasone, mannitol, and acyclovir were started, and ceftriaxone was continued. Five days later, the mother recalled that the patient was bitten by a feral cat. Thus, human rabies immunoglobulin serum was administered immediately. However, 2 days later, the patient died. Post-mortem brain direct immunofluorescence study confirmed human rabies. Awareness campaigns can be lifesaving since more than 99% of deaths can be prevented if timely treatment is provided.
Neurodevelopmental Outcomes in Medically Fragile Infant Populations
Authors: Kiderman Miryam , Zaccario Michele , Rosenthal Lisa , Sklamberg Felice , Saviano Jenna , Howell Heather
Published: February 2025

Medical advances have enabled infants born premature or with congenital cardiac defects (CHD) to have increased lifespans. Understanding neurodevelopmental profiles and outcomes enhances the identification of potential challenges and helps pinpoint targets for early intervention, starting from infancy. Neurodevelopmental vulnerabilities are documented for both populations, with developmental delays, including cognitive, motor, language, neurosensory, and social-emotional development. Whereas neurodevelopmental follow up for premature infants is established, similar protocols are not typically in place for CHD infants. The current study aims to identify trends in these at-risk populations to better understand developmental trajectories and provide recommendations for follow up. Outcome measures of cognitive, motor, language functioning from the Bayley Scales of Infant and Toddler Development, Third Edition, along with growth measurements and cardiac diagnoses from 322 participants, aged 6 months (cardiac) and 6 months age-corrected (premature infant) were collected. Similarities in functioning were identified. Findings indicate associations between CHD diagnosis and motor development, prematurity and severity of outcomes, and head circumference and cognitive functioning. Cardiac diagnosis severity alone was not associated with outcome severity. These findings expand previous literature identified similar at-risk profiles and needs. Continued follow up through school age is recommended to identify subtle delays that may emerge throughout development.
Novel Regulators of GVHD Revealed Through Microbiome and Metabolome Patterns Across Distinct Intestinal Regions.
Authors: Lauder Emma , Kiledal Erik Anders , Maneix Laure , Furnholm Teal , Santibanez Ana , Zhao Dongchang , Sun Yaping , Dick Gregory J , Reddy Pavan
Published: February 2025

Microbial dysbiosis and metabolite changes in the gastro-intestinal (GI) tract have been linked to pathogenesis and severity of many diseases, including graft-versus-host disease (GVHD), the major complication of allogeneic hematopoietic stem cell transplantation (HCT). However, published studies have only considered the microbiome and metabolome of excreted stool and do not provide insight into the variability of microbial community and metabolite composition throughout the GI tract or the unique temporal dynamics associated with different gut locations. Because such geographical variations are known to influence disease processes, we utilized a multi-omics approach to characterize the microbiome and metabolite profiles of gut contents from different intestinal regions in well-characterized mouse models of GVHD. Our analysis validated analyses from excreted stool, but importantly, uncovered new biological insights from the microbial and metabolite changes between syngeneic and allogeneic hosts that varied by GI location and time after transplantation. Our integrated analysis confirmed the involvement of known metabolic pathways, including SCFA synthesis and bile acid metabolism, and identified additional functional genes, pathways, and metabolites, such as amino acids, fatty acids, and sphingolipids, linked to GI GVHD. Finally, we validated a biological relevance for one such newly identified microbial metabolite, phenyl lactate, that heretofore had not been linked to GI GVHD. Thus, our analysis of the geographic variability in the intestinal microbiome and metabolome offers new insights into GI GVHD pathogenesis and potential for novel therapeutics.
Ibrutinib Lead-in followed by Venetoclax Plus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia - SAKK 34/17
Authors: Condoluci Adalgisa , Romano Ilaria , Dietrich Daniel , Pini Katia , Stussi Georg , Müller Gisela , Cantoni Nathan , Cathomas Richard , Mey Ulrich J.M. , Widmer Anouk Andrea , Zenz Thorsten , Gregor Michael , Heim Dominik , Andres Martin , Benz Rudolf , Rossi Davide
Published: February 2025

The rationale for combining ibrutinib and venetoclax (IV) in chronic lymphocytic leukemia (CLL) treatment lies in their complementary mechanisms of action. Studies investigating IV typically begin with a short initial course of ibrutinib, followed by venetoclax introduction for a limited duration, typically 12 months. SAKK34/17 (NCT03708003) is a single-arm, open-label, multicenter, phase 2 trial evaluating the effectiveness of a modified IV schedule in patients with relapsed/refractory (R/R) CLL. No prior exposure to BTK- or BCL2-inhibitors was allowed. The lead-in phase with ibrutinib was extended to six months to reduce the tumor burden and related tumor lysis syndrome (TLS) risk. Additionally, the treatment phase with IV is prolonged to a minimum of 24 months to enhance the undetectable minimal residual disease (uMRD, 10-4) rate. The primary endpoint was the rate of complete response or complete response with incomplete bone marrow recovery (CR/CRi) with uMRD in both bone marrow (BM) and peripheral blood (PB). Secondary endpoints included assessing the proportion of patients who transitioned to a low-risk category for TLS after receiving ibrutinib lead-in. Out of the 30 patients with R/R CLL who were enrolled, 40.0% achieved a status of uMRD CR/CRi according to the intention-to-treat analysis, and 53.3% showed uMRD in the BM and PB. Following the lead-in period with ibrutinib, 57.1% of patients achieved a low-risk for TLS. At cycle 31, the progression-free survival rate was 89.9%. These results contribute to the increasing body of evidence supporting the idea that a longer IV duration is beneficial for enhancing therapeutic effectiveness.
Magrolimab plus azacitidine vs physician's choice for untreated TP53-mutated acute myeloid leukemia: the ENHANCE-2 study
Authors: Zeidner Joshua F. , Sallman David A. , Récher Christian , Daver Naval G. , Leung Anskar YH , Hiwase Devendra K. , Subklewe Marion , Pabst Thomas , Montesinos Pau , Larson Richard A , Wilde Lindsay , Enjeti Anoop K. , Kawashima Ichiro , Papayannidis Cristina , O'Nions Jenny , Johnson Lisa , Dong Mei , Huang Julie , Bagheri Taravat , Hacohen-Kleiman Gal , Lee Calvin , Vyas Paresh
Published: February 2025

Patients with TP53-mutated acute myeloid leukemia (AML) have an extremely poor prognosis, necessitating new treatments. The global, randomized, phase 3 ENHANCE-2 trial evaluated the anti-CD47 monoclonal antibody magrolimab plus azacitidine (Magro/Aza) for previously untreated TP53-mutated AML. Patients determined inappropriate for intensive therapy were randomized to receive Magro/Aza or venetoclax plus azacitidine (Ven/Aza); those appropriate for intensive therapy were randomized to receive Magro/Aza or 7+3 induction chemotherapy. Primary endpoint was overall survival (OS) in the non-intensive arm. At interim analysis, non-intensive-arm OS hazard ratio (HR) between treatment groups was 1.191 (95% CI, 0.744-1.906), meeting the study's definition for futility and resulting in study termination. At final analysis, median OS was 4.4 vs 6.6 months (HR, 1.132; 95% CI, 0.783-1.637; P = .5070) in the non-intensive arm (n = 205) and 7.3 vs 11.1 months (HR, 1.434; 95% CI, 0.635-3.239; P = .3798) in the intensive arm (n = 52) between Magro/Aza and control groups, respectively. Incidences of grade ≥3 adverse events (AEs) were similar across Magro/Aza and control groups (non-intensive, n = 194: 96.9% and 95.9%; intensive, n = 50: 92.6% and 95.7%), including grade ≥3 anemia (non-intensive: 27.1% and 23.5%; intensive: 25.9% and 21.7%). Grade ≥3 infections were observed in 50.0% and 53.1% of patients in the non-intensive arm and 44.4% and 65.2% of intensive arm patients. ENHANCE-2 did not meet its primary endpoint of OS in TP53-mutated AML but provides important data informing future studies in this challenging population. This trial was registered at www.clinicaltrials.gov as #NCT04778397.
Up-front Blinatumomab Improves MRD Clearance and Outcome in Adult Ph− B-lineage ALL: the GIMEMA LAL2317 Phase 2 Study
Authors: Bassan Renato , Chiaretti Sabina , Della Starza Irene , Santoro Alessandra , Spinelli Orietta , Tosi Manuela , Elia Loredana , Cardinali Deborah , De Propris Maria Stefania , Piccini Matteo , Lussana Federico , Annunziata Mario , Chiusolo Patrizia , Zappasodi Patrizia , Borlenghi Erika , Leoncin Matteo , Califano Catello , Bocchia Monica , Di Raimondo Francesco , Grimaldi Francesco , Tiribelli Mario , Candoni Anna , Lico Albana , Audisio Ernesta , Lunghi Monia , Mianulli Anna Maria , Di Trani Mariangela , Arena Valentina , Messina Monica , Piciocchi Alfonso , Fazi Paola , Rambaldi Alessandro , Foà Robin
Published: February 2025

The GIMEMA LAL2317 protocol investigated the frontline chemotherapy-blinatumomab combination in adult Philadelphia- CD19+ B-lineage acute lymphoblastic leukemia (Ph- B-ALL) to improve minimal residual disease (MRD) response and clinical outcome. Two cycles of intravenous blinatumomab were administered after chemotherapy cycles 3 and 6. The primary endpoint was the rate of molecular MRD negativity following blinatumomab 1. One hundred and forty-nine patients were enrolled (median age 41 years, range18-65); 132 entered remission, 122 received blinatumomab and 109 had a pre- and post-blinatumomab 1 MRD assessment. MRD negativity increased from 72% to 93% (P<0.001) after blinatumomab, with 23/30 MRD+ patients (73%) becoming MRD-, fulfilling the primary endpoint. At a median follow-up of 38.1 months (0.5-62.8), the median overall and disease-free survivals (OS, DFS) were not reached and the estimated 3-year OS and DFS were 71% and 65%, with an excellent outlook for the patients aged 18-40 years who achieved an early MRD negativity (DFS 92%). Pre-blinatumomab MRD predicted a worse outcome, especially in genetics high-risk patients. Notably, the 3-year survival of blinatumomab-treated patients was 82%. Survival and relapse rates were 91% and 15% in patients assigned to standard chemotherapy, 59% and 35% in patients assigned to HSCT, and 69% and 19% in transplant recipients. Blinatumomab toxicity was manageable, with only 8 permanent discontinuations. This chemotherapy-blinatumomab risk-oriented program yielded remarkable results that need further improvement in higher-risk patients displaying early MRD persistence. Blinatumomab should be considered as a standard component of induction/consolidation for adult Ph- B-ALL. ClinicalTrials.gov # NCT03367299.
Sustained bone marrow and imaging MRD negativity for 3 years drives discontinuation of maintenance post ASCT in myeloma
Authors: Terpos Evangelos , Malandrakis Panagiotis , Ntanasis-Stathopoulos Ioannis , Kostopoulos Ioannis V , Eleutherakis-Papaiakovou Evangelos , Kanellias Nikolaos , Spiliopoulou Vassiliki , Migkou Magdalini , Fotiou Despina V , Theodorakakou Foteini , Kastritis Efstathios , Gavriatopoulou Maria , Tsitsilonis Ourania , Dimopoulos Meletios-Athanasios A.
Published: February 2025

Discontinuation of lenalidomide maintenance post autologous transplantation (ASCT) is a burning question within the myeloma (MM) community, especially after the inclusion of MRD in the disease response criteria. In this prospective study, we evaluated the conversion to MRD positivity, the treatment-free survival (TFS) and the progression-free survival (PFS) in 52 MM patients, who discontinued lenalidomide maintenance, after achievement of sustained bone marrow and imaging MRD negativity for three years. Patients who developed MRD positivity after lenalidomide discontinuation, restarted lenalidomide maintenance at the same dose. The median follow-up from lenalidomide discontinuation was 3 years. Overall, 12 (23%) patients obtained MRD positivity and restarted lenalidomide maintenance. Only four (7.6%) patients progressed; 3 had a biochemical progression and one had a clinical progression. The overall median PFS was not reached, while the 7-year PFS from diagnosis was 90.2%. The 1-, 2- and 3-year TFS rates were 93.9%, 91.6% and 75.8%, respectively, whereas the 1-, 2- and 3-year landmark PFS rates from maintenance discontinuation (study entrance) were 96.0%, 96.0% and 92.9%, respectively. There were no statistically significant associations between age, gender, R2-ISS, type of induction therapy and use of consolidation therapy and the effect outcomes of PFS, TFS. We conclude that MRD discontinuation after 3-year sustained marrow and imaging MRD negativity is associated with low rates of MRD conversion and progressive disease. Thus, in the era of modern anti-myeloma treatments, a subgroup of patients may remain treatment free while in complete remission, without jeopardizing disease response.
Correlation between double-J stent length and patient body height: a randomized, prospective cohort study
Authors: Ahmed Mohd Hamid Shafique , Arora Amandeep , Hambarde Pramol , Sawant Ajit , Pawar Prakash , Mulla Asif
Published: February 2025

Background

To evaluate the correlation between double-J (DJ) ureteric stent length and patient body height compared with direct ureteric length (DUL).

Methods

This randomized, prospective cohort study was conducted at a tertiary care center in the Department of Urology, Mumbai, Maharashtra, India, between January 2017 and January 2018. Male and female patients above the age of 12 years who presented with urolithiasis and required double-J (DJ) stenting following endoscopic lithotripsy (URSL, PCNL, RIRS) were enrolled in the study. In Group 1, stent selection was based on the direct ureteric length (DUL), and in the other group (Group 2), double-J ureteric stents were inserted based on the patient’s body height. All patients underwent postoperative X-ray kidney-ureter-bladder examination on day 3 to assess the graded position of the double-J (DJ). The relationship between the graded position of the double-J stents, stent compliance, and patient discomfort was evaluated at a follow-up visit 2 weeks postoperatively.

Results

A total of 222 patients were included in the study, with 113 patients in group 1 stented according to DUL and 109 patients in group 2 stented according to height. The mean age of the patients was 42.12 years (± 15.05), with Group 1 having a slightly longer mean DUL of 24.11 cm (± 1.27) compared to Group 2, which had a mean DUL of 23.05 (± 1.74) (P < 0.001). Group 1 exhibited a higher proportion of symptomatic patients than group 2, with a greater mean number of symptoms per patient (1.76 vs. 1.07, p = 0.0005). Group 1 also reported more severe symptoms than group 2 (2.62 vs. 2.05, p = 0.0188). The analysis revealed significant positive correlations between the DUL and both Height and weight (r = 0.316; p = 0.0001). However, no statistically significant correlations were observed between DUL, body weight, and body mass index (BMI).

Conclusion

Our study suggests that Height-based DJ stent selection is superior to direct DUL measurement and height as a predictor of DUL, providing means to predict DUL based on the patient’s height.
Quantitative levels of interferon gamma as a biomarker in the aqueous and serum samples of infectious and noninfectious uveitis patients
Authors: Shaban Sahar Saad Eldeen Mohamed , Safwat Hend Mohammed , Abdelmohymen Abeer Mohammed , Hassan Donia Ahmed , Mansour Mona Nabeh , Mohammed Hanan Said , Seliem Nora , El Attar Shahinaz , Amin Doaa Refaat , Khirala Seham Kamal Ahmed , Ghamry Aya Ahmed , Anany Mona Gamal El Din Al , Mohammed Shaymaa Fathy
Published: February 2025

Background

To study the utility of interferon gamma (IFN-γ) as a differentiating biomarker by assessing the aqueous humour and serum of patients with infectious and noninfectious uveitis.

Methods

A total of 40 patients with acute uveitis were divided into 2 groups (18 patients with infectious uveitis and 22 patients with noninfectious uveitis). All the subjects underwent a full ophthalmological examination. Aqueous humour (AqH) and serum samples were collected from uveitis patients. The quantitative levels of IFN-γ in aqueous medium and serum were measured by means of an enzyme-linked immunosorbent assay (ELISA).

Results

The quantitative level of IFN-γ in the aqueous humour was significantly greater (87.5 ± 81) (pg/ml) in infectious uveitis patients than in noninfectious uveitis patients (37.3 ± 9.9) (pg/ml) (p value = 0.006). However, the serum IFN-γ level (pg/ml) did not significantly differ between these groups (p value = 0.279). Thus, the IFN-γ level in the aqueous humour can be used to discriminate between infectious and noninfectious uveitis with 33.3% sensitivity and 100% specificity.

Conclusion

Aqueous IFN-γ can be used as a biomarker for differentiating between infectious and noninfectious uveitis.
Biological and therapeutic implications of sex hormone-related gene clustering in testicular cancer
Authors: Törzsök Péter , Santer Frédéric R. , Kunz Yannic , van Creij Nils C. H. , Tymoszuk Piotr , Klinglmair Gerald , Culig Zoran , Pichler Renate
Published: February 2025

Background

Gonadotropin dysregulation seems to play a potential role in the carcinogenesis of testicular germ cell tumor (TGCT). The aim of this study was to explore the expression of specific genes related to sex hormone regulation, synthesis, and metabolism in TGCT and to define specific hormonal clusters. Two publicly available databases were used for this analysis (TCGA and GSE99420). By means of hard-threshold regularized KMEANS clustering, we assigned TGCT samples into four clusters defined in respect to different expression of the sex hormone-related genes. We analysed clinical data, protein and gene expression, signaling regarding hormonal clusters. Based on whole-transcriptome gene expression, prediction of anti-cancer drug response was made by RIDGE models.

Results

Cluster #1 (12–16%) consisted primarily of non-seminomatous germ cell tumor (NSGCT), characterized by high expression of PRL, GNRH1, HSD17B2 and SRD5A1. Cluster #2 (42–50%) included predominantly seminomas with high expression of SRD5A3, being highly infiltrated by T and B cells. Cluster #3 (8.3–18%) comprised of NSGCT with high expression of CGA, CYP19A1, HSD17B12, HSD17B1, SHBG. Cluster #4 (23–30%), which consisted primarily of NSGCT with a small fraction of seminomas, was outlined by increased expression of STAR, POMC, CYP11A1, CYP17A1, HSD3B2 and HSD17B3. Elevated fibroblast levels and increased extracellular matrix- and growth factor signaling-related gene signature scores were described in cluster #1 and #3. In the combined model of progression-free survival, S2/S3 tumor marker status, hormonal cluster #1 or #3 and teratoma histology, were independently associated with 25–30% increase of progression risk. Based on the increased receptor tyrosine kinase and growth factor signaling, cluster #1, #3 and #4 were predicted to be sensitive to tyrosine kinase inhibitors, FGFR inhibitors or EGFR/ERBB inhibitors. Cluster #2 and #4 were responsive to compounds interfering with DNA synthesis, cytoskeleton, cell cycle and epigenetics. Response to apoptosis modulators was predicted only for cluster #2.

Conclusions

Hormonal cluster #1 or #3 is an independent prognostic factor regarding poor progression-free survival. Hormonal cluster assignment also affects the predicted drug response with cluster-dependent susceptibility to specific novel therapeutic compounds.
Data-driven projections of candidate enhancer-activating SNPs in immune regulation
Authors: Hoffmann Markus , Vaz Tiago , Chhatrala Shreeti , Hennighausen Lothar
Published: February 2025

Background

Millions of single nucleotide polymorphisms (SNPs) have been identified in humans, but the functionality of almost all SNPs remains unclear. While current research focuses primarily on SNPs altering one amino acid to another one, the majority of SNPs are located in intergenic spaces. Some of these SNPs can be found in candidate cis-regulatory elements (CREs) such as promoters and enhancers, potentially destroying or creating DNA-binding motifs for transcription factors (TFs) and, hence, deregulating the expression of nearby genes. These aspects are understudied due to the sheer number of SNPs and TF binding motifs, making it challenging to identify SNPs that yield phenotypic changes or altered gene expression.

Results

We developed a data-driven computational protocol to prioritize high-potential SNPs informed from former knowledge for experimental validation. We evaluated the protocol by investigating SNPs in CREs in the Janus kinase (JAK) – Signal Transducer and Activator of Transcription (-STAT) signaling pathway, which is activated by a plethora of cytokines and crucial in controlling immune responses and has been implicated in diseases like cancer, autoimmune disorders, and responses to viral infections. The protocol involves scanning the entire human genome (hg38) to pinpoint DNA sequences that deviate by only one nucleotide from the canonical binding sites (TTCnnnGAA) for STAT TFs. We narrowed down from an initial pool of 3,301,512 SNPs across 17,039,967 nearly complete STAT motifs and identified six potential gain-of-function SNPs in regions likely to influence regulation within the JAK-STAT pathway. This selection was guided by publicly available open chromatin and gene expression data and further refined by filtering for proximity to immune response genes and conservation between the mouse and human genomes.

Conclusion

Our findings highlight the value of combining genomic, epigenomic, and cross-species conservation data to effectively narrow down millions of SNPs to a smaller number with a high potential to induce interferon regulation of nearby genes. These SNPs can finally be reviewed manually, laying the groundwork for a more focused and efficient exploration of regulatory SNPs in an experimental setting.
Impact of perioperative anticoagulation management on free flap survival in reconstructive surgery: a retrospective analysis
Authors: Torabi Saeed , Overbeek Remco , Dusse Fabian , Stoll Sandra E. , Schroeder Carolin , Zinser Max , Zirk Matthias
Published: February 2025

Background

Despite advancements in surgical techniques and perioperative care for free flap reconstructive surgery, concerns persist regarding the risk of free flap failure, with thrombosis and bleeding being the most common complications that can lead to flap loss. While perioperative anticoagulation management is crucial for optimizing outcomes in free flap reconstructive surgery, standardized protocols remain lacking. This study aims to investigate the role of anticoagulation and perioperative practices in free flap reconstructive surgery and their impact on surgical outcomes.

Methods

This retrospective, single-center study included all adult patients undergoing free flap surgery from 2009 to 2020. Patients were retrospectively divided based on intraoperative (UFH or no UFH) and postoperative anticoagulation management (UFH only, Aspirin and UFH, Aspirin only). The relationship between anticoagulation protocols, PTT values, and flap survival was assessed.

Results

A total of 489 free flap surgeries were included. Most flaps were taken from the upper extremity (49.5%), primarily for tumor-related reconstructions (85.7%). Flap loss occurred in 14.5% of cases, with a median time to flap loss of 3 days post-surgery. Intraoperative UFH (20 IU/kg) was administered to 63.6% of patients and significantly predicted flap survival (OR = 0.45, 95% CI [0.24, 0.82]). PTT values on day 1 post-surgery were significantly related to flap survival (P = 0.03), with each unit increase reducing the relative probability of flap loss by 5.2%. There was no significant difference in flap survival between patients treated with heparin alone and those treated with both heparin and aspirin. The small sample size in the aspirin-only group limited the statistical relevance of this subgroup.

Conclusion

Our findings highlight the importance of intraoperative UFH and PTT-guided postoperative management in improving free flap survival. Standardized anticoagulation protocols are essential for enhancing outcomes in free flap reconstructive surgery.
T-cell activation of Toxoplasma gondii positive donors by maltodextrin nanoparticles formulated with killed Toxoplasma gondii
Authors: Vargas-Montes Monica , Fasquelle François , Cardona Nestor Ivan , Gómez-Marín Jorge Enrique , Betbeder Didier
Published: February 2025

Nasal vaccination with killed tachyzoites from Toxoplasma gondii loaded in lipidated maltodextrin nanoparticles (NPL/T.gondii) has been shown to induce protection against lethal T.gondii infection in mice, sheep and squirrel monkeys. This protection was related to a unique T-cell mediated response (Th1 and Th17). In immunocompetent humans T.gondii infection is generally asymptomatic but leads to the formation of cysts in several organs. These cysts may reactivate during episodes of immunosuppression, owing to a Th1 immune exhaustion, leading to numerous complications. The objectives of the current study were to assess whether NPL/T. gondii vaccine can stimulate a specific IFN-γ secretion on peripheral blood mononuclear cells (PBMC) of Toxo-positive donors, in order to potentially prevent reactivation of the parasite. By using enzyme-linked immunospot (ELISpot) assays, the frequency of IFN-γ producing cells was quantified after 72 h of stimulation. This stimulation was specific of the Toxo + donors’ memory T-cells. The uptake of this formulation by PBMCs was evaluated using flow cytometry, more particularly in T lymphocytes (CD3 + CD4 + and CD3 + CD8 +), B lymphocytes (CD3- CD19 +) and natural killer cells (CD3- CD56 +). Surprisingly, a lower antigen uptake was observed in all cell populations from Toxo + donors compared with the seronegative ones. Further in vitro analysis revealed that the early specific IFN-γ secretion by stimulated memory cells from Toxo-positive donors inhibited the endocytosis mechanism, therefore lowering their own vaccine uptake. These results suggest that NPL/T.gondii formulation can specifically trigger the existing Th1 immune response in positive donors, reinforcing their ability to control infection and reactivation.
Prescription of essential medication during the final hospitalization of patients with heart failure or cancer
Authors: González-Jaramillo Valentina , Hagemann Monika , Hunziker Lukas , Maessen Maud , Eychmüller Steffen
Published: February 2025

Background

Four medication types—opioids, benzodiazepines, anticholinergics, and antipsychotics—have been proposed as essential for patients in their final days, regardless of their primary diagnosis. These drugs are typically prescribed for individuals with cancer who are under specialized palliative care (PC+). However, it is not known whether their usage is equally common for patients with other chronic and progressive conditions, such as heart failure (HF), or for those who are not under specialized palliative care (PC-).

Aim

To assess the prescription frequency of each of the four medication types during the final hospitalization of patients with HF and compare it with the prescription frequency in patients with cancer (CA), considering both PC + and PC- patients in each disease group.

Methods

A retrospective cohort study included all patients dying in a tertiary hospital between 2016 and 2022. We created three disease groups – “HF,” “CA,” and “HF&CA” – splitting each of them into two groups, depending on whether they received PC. So there were a total of six groups – “HF PC+”, “HF PC-“, “CA PC+”, “CA PC-”, “HF&CA PC+”, and “HF&CA PC-”.

Results

Of the 3,874 patients, 1,921 (59%) had cancer exclusively, 371 (10%) had heart failure exclusively, and 691 (18%) had both. The median length of stay was 9 days (IQR 2–16). Within each diagnosis group, PC + patients had a higher prescription frequency for each medication type than PC- patients. For example, patients who received PC had 12 times the odds of being prescribed opioids than those who did not receive it (p < 0.05). Among the six groups, the highest prescription frequency of opioids, benzodiazepines, and anticholinergics was seen in the “HF PC+” group and the lowest in the “HF PC-” group. Antipsychotics were prescribed less frequently in the “HF PC-” and the “CA PC-” groups and were mainly prescribed in the “CA PC+” group.

Conclusion

Across the diagnostic groups, a notable difference in the prescription of the four medication types was observed between PC + and PC- patients. This difference was more pronounced among patients with HF (without cancer).
Context sensitive mindfulness: lessons from graduates of a professional training in South Africa
Authors: Whitesman Simon , Mash Robert
Published: February 2025

Objective

The study aimed to evaluate the implementation of mindfulness based interventions, in different community settings in South Africa, by graduates of a two-year mindfulness training course, and to explore the challenges involved in adapting to the local context.

Methods

This was a descriptive exploratory qualitative study using semi-structured interviews. Ten graduates of a two-year training in mindfulness-based interventions (MBIs) were identified using purposeful criterion-based sampling based on their implementation of adapted MBIs in communities that represented the systemic social, economic and health challenges affecting a majority of South Africans.

Results

Previous and ongoing trauma is pervasive in South Africa which significantly affects the quality of lived experience for many individuals and families. Teachers who offered mindfulness-based approaches within these communities needed to hold a high level of sensitivity to pre-existing and ongoing trauma and signs of traumatic abreaction to effectively and skilfully deliver these interventions. Context sensitive adaptations needed to be implemented to programme structure, such as length of sessions, prioritisation of curricular elements and duration of mindfulness practices, along with in-the-moment flexible responsiveness such as ending a formal practice ealier than planned, or responding to the emotional needs of an individual. This was supported by the creation of a robust and compassionate holding environment, a safe and secure space in which attuned relationality supported co- and self-regulation and the internalisation of mindfulness skills.

Conclusion

Mindfulness can be a valuable practice in diverse settings in South Africa, including communities affected by previous and current trauma, and the training curriculum in this context requires high levels of sensitivity to these conditions and must prioritise a safe and compassionate environment in which to learn.
Minimum and optimal combined variations in sleep, physical activity, and nutrition in relation to all-cause mortality risk
Authors: Stamatakis Emmanuel , Koemel Nicholas A. , Biswas Raaj K. , Ahmadi Matthew N. , Allman-Farinelli Margaret , Trost Stewart G. , Inan-Eroglu Elif , del Pozo Cruz Borja , Bin Yu Sun , Postnova Svetlana , Duncan Mitch J. , Dumuid Dorothea , Brown Helen , Maher Carol , Fontana Luigi , Simpson Stephen , Cistulli Peter A.
Published: February 2025

Background

Sleep, physical activity, and nutrition (SPAN) are critical behaviours for health, although they have traditionally been studied separately. We examined the combined associations of SPAN and the minimum between-individual variations associated with meaningfully lower all-cause mortality risk.

Methods

This prospective cohort analysis included 59,078 participants from the UK Biobank (median age: 64.0 years; 45.4% male) who wore trackers for 7 days and self-reported dietary data. Wearable-measured sleep (hours/day) and moderate to vigorous physical activity (MVPA; mins/day) were calculated using a machine learning based schema. A 10-item diet quality score (DQS) assessed the intake of vegetables, fruits, fish, dairy, whole grains, vegetable oils, refined grains, processed and unprocessed meats, and sugary beverages (0–100 for all components with higher values indicating higher quality). Cox proportional hazards models were used to estimate hazard ratios (HR) for all-cause mortality risk across 27 separate joint tertile combinations of SPAN behaviours with the lowest tertile for all three as the referent group. For more granular clinical interpretations, we examined combined incremental dose–response changes of the SPAN behaviours using the 5th percentile of each behaviour as the referent point.

Results

Over the 8.1-year median follow-up time, 2,458 mortality events occurred. Compared to the referent group of combined SPAN exposure (lowest tertiles for all three), the optimal SPAN combination involving moderate sleep duration (7.2–8.0 h/day), high MVPA (42–103 min/day), and a DQS between 57.5 and 72.5 was associated with an HR of 0.36 (95% CI: 0.26–0.50). Relative to the 5th percentile of sleep (5.5 h/day), physical activity (7.3 min/day), and nutrition (36.9 DQS), a theoretical minimum combined increase of 15 min/day of sleep, 1.6 min/day MVPA, and 5 DQS points (corresponding to e.g., extra 1/2 serving of vegetables per day or 1 less serving of processed meat per week) was associated with 10% lower all-cause mortality risk (0.90; 0.88–0.93). Combined increases of 75 min/day of sleep, 12.5 min/day MVPA, and 25 DQS points were associated with 50% lower all-cause mortality risk (0.50; 0.44–0.58).

Conclusions

This study highlights the potential health value of subtle combined SPAN modification in relation to mortality risk and expands opportunities for more holistic recommendations.
Pig tail length is associated with the prevalence of tail malformations but not with inflammation of the tail
Authors: Egerer Christiane , Gerhards Katharina , Becker Sabrina , Engel Petra , König Sven , Reiner Gerald
Published: February 2025

Background

Assuming that tail length is associated with the prevalence of tail biting, attempts are being made to shorten tails by genetic selection in order to avoid the painful procedure of docking. However, undesirable side effects such as kinky tails and inflammatory changes may occur. The aim of the present study was to clinically quantify in a population with known segregation of tail length, i) its variability, ii) possible associations with kinked tails and iii) possible associations of tail length and kinks with inflammation of the tail using 348 piglets at day 3 (undocked) and 39 (docked tails) of life.

Results

The relative tail length (tail tip to tail base/tail tip to ear base × 100) varied between 20.3 and 31.3%. A reduced tail length was associated with kinked tails. Piglets with the shortest tails had 28% kinked tails, 5.6 times more than the piglets with the longest tails. The tails showed high prevalence of inflammation both on day 3 and on the docked tails on day 39. Overall, these were not associated with tail length or kinked tails. Only necrosis of the tail was significantly more frequent in the kinked tails than in the normal tails. Sow line, sow ID and boar ID significantly affected relative tail length, which may suggest a genetic cause.

Conclusion

Based on the phenotypic variation found in the present study, it seems possible to influence tail length through breeding. It remains to be seen whether the available potential is sufficient to actually reduce tail biting. At the same time, a higher incidence of kinked tails and necrosis is to be expected.
The blood–brain barriers: novel nanocarriers for central nervous system diseases
Authors: Liu Jiajun , Wang Ting , Dong Jian , Lu Yuan
Published: February 2025

The central nervous system (CNS) diseases are major contributors to death and disability worldwide. However, the blood–brain barrier (BBB) often prevents drugs intended for CNS diseases from effectively crossing into the brain parenchyma to deliver their therapeutic effects. The blood–brain barrier is a semi-permeable barrier with high selectivity. The BBB primarily manages the transport of substances between the blood and the CNS. To enhance drug delivery for CNS disease treatment, various brain-based drug delivery strategies overcoming the BBB have been developed. Among them, nanoparticles (NPs) have been emphasized due to their multiple excellent properties. This review starts with an overview of the BBB’s anatomical structure and physiological roles, and then explores the mechanisms, both endogenous and exogenous, that facilitate the NP passage across the BBB. The text also delves into how nanoparticles' shape, charge, size, and surface ligands affect their ability to cross the BBB and offers an overview of different nanoparticle classifications. This review concludes with an examination of the current challenges in utilizing nanomaterials for brain drug delivery and discusses corresponding directions for solutions. This review aims to propose innovative diagnostic and therapeutic approaches for CNS diseases and enhance drug design for more effective delivery across the BBB.

Graphical abstract
The properties of TREM1 and its emerging role in pain-related diseases
Authors: Fan Zhenzhen , Sun Songtang , Wang Longde , Ge Zhaoming
Published: February 2025

The TREM1 receptor, a member of the TREMs family, is expressed by myeloid cells and functions as an initiator or enhancer of the inflammatory response, playing a pivotal role in the regulation of inflammation. In recent years, it has been found that TREM1-mediated inflammatory response is involved in the regulation of pain-related diseases. This article provides an extensive review on the structural characteristics and distribution patterns, ligand, signaling pathways, inhibitors, and pathophysiological roles of TREM1 in pain disorders aiming to further elucidate its biological function and offer novel insights for clinical interventions targeting pain-related diseases.