BACKGROUND: Limited licensed medications are available for multiple sclerosis (MS) in pediatric patients. OBJECTIVE: To evaluate the efficacy, safety, and tolerability of alemtuzumab in pediatric patients with relapsing-remitting multiple sclerosis (RRMS) and disease activity on prior disease-modifying therapies (DMTs). METHODS: LemKids was a multicenter, multinational, single-arm, open-label, switch (from ongoing DMT to alemtuzumab treatment) study in pediatric RRMS patients (aged 10-<18 years), with disease activity on DMT. The primary endpoint was a comparison of the number of new/enlarging T2 lesions on the magnetic resonance imaging of the brain between the prior-DMT period and alemtuzumab treatment. RESULTS: This study was prematurely terminated due to low enrollment and an European Medicines Agency Article-20 pharmacovigilance review of alemtuzumab in adult RRMS. Of 46 screened patients, 16 were enrolled; 12 completed prior-DMT treatment period; 11 received alemtuzumab of whom 7 completed treatment. Patients on alemtuzumab developed fewer new/enlarging T2 lesions compared with prior-DMT (7 vs 178, relative risk (95% confidence interval): 0.04 (0.01-0.14)). No significant pharmacodynamic changes or safety concerns were noted in this limited dataset. CONCLUSION: Alemtuzumab treatment was associated with a low number of new/enlarging T2 lesions in pediatric patients with RRMS and was safe and well tolerated in seven patients during infusion and the initial 4 months.

• MeSH
• Alemtuzumab * adverse effects   MeSH
• Child MeSH
• Immunologic Factors * adverse effects   administration & dosage   MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Adolescent MeSH
• Multiple Sclerosis, Relapsing-Remitting * drug therapy   diagnostic imaging   MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH

Since 2017, targeted therapies combined with conventional intensive chemotherapy have started to improve outcomes of patients with acute myeloid leukemia (AML). However, even before these innovations, outcomes with intensive chemotherapy had improved, which has not yet been extensively studied. Thus, we used a large pan-European multicenter dataset of the HARMONY Alliance to evaluate treatment-time dependent outcomes over two decades. In 5,359 AML patients, we compared the impact of intensive induction therapy on outcome over four consecutive 5-year calendar periods from 1997 to 2016. During that time, the 5-year survival of AML patients improved significantly, also across different genetic risk groups. In particular, the 60-day mortality rate dropped from 13.0% to 4.7% over time. The independent effect of calendar periods on outcome was confirmed in multivariate models. Improvements were documented both for patients <60 and ≥60 years old, and in those treated with and without consolidating allogeneic hematopoietic stem cell transplantation (alloHCT). While survival of AML elderly patients remains poor, patients ≥60 years old overall have a 20% survival benefit at 5 years if they receive an alloHCT. While further outcome improvement in intensively treated AML patients will likely be driven by targeted treatment approaches, this pan-European HARMONY dataset can serve as a multicenter comparator for future studies.

• MeSH
• Leukemia, Myeloid, Acute * mortality   therapy   diagnosis   epidemiology   MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Prognosis MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Hematopoietic Stem Cell Transplantation MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Geographicals
• Europe MeSH

During development, tooth germs undergo various morphological changes resulting from interactions between the oral epithelium and ectomesenchyme. These processes are influenced by the extracellular matrix, the composition of which, along with cell adhesion and signaling, is regulated by metalloproteinases. Notably, these include matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), and a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTSs). Our analysis of previously published scRNAseq datasets highlight that these metalloproteinases show dynamic expression patterns during tooth development, with expression in a wide range of cell types, suggesting multiple roles in tooth morphogenesis. To investigate this, Marimastat, a broad-spectrum inhibitor of MMPs, ADAMs, and ADAMTSs, was applied to ex vivo cultures of mouse molar tooth germs. The treated samples exhibited significant changes in tooth germ size and morphology, including an overall reduction in size and an inversion of the typical bell shape. The cervical loop failed to extend, and the central area of the inner enamel epithelium protruded. Marimastat treatment also disrupted proliferation, cell polarization, and organization compared with control tooth germs. In addition, a decrease in laminin expression was observed, leading to a disruption in continuity of the basement membrane at the epithelial-mesenchymal junction. Elevated hypoxia-inducible factor 1-alpha gene (Hif-1α) expression correlated with a disruption to blood vessel development around the tooth germs. These results reveal the crucial role of metalloproteinases in tooth growth, shape, cervical loop elongation, and the regulation of blood vessel formation during prenatal tooth development.NEW & NOTEWORTHY Inhibition of metalloproteinases during tooth development had a wide-ranging impact on molar growth affecting proliferation, cell migration, and vascularization, highlighting the diverse role of these proteins in controlling development.

• MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit metabolism   genetics   MeSH
• Matrix Metalloproteinase Inhibitors pharmacology   MeSH
• Hydroxamic Acids pharmacology   MeSH
• Metalloproteases metabolism   genetics   MeSH
• Molar embryology   growth & development   metabolism   enzymology   MeSH
• Morphogenesis MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Odontogenesis * MeSH
• Cell Proliferation * MeSH
• Gene Expression Regulation, Developmental MeSH
• Tooth Germ embryology   metabolism   enzymology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

INTRODUCTION: Impulsivity and aggression are often interlinked behavioral traits that have major implications for our society. Therefore, the study of this phenomenon and derivative interventions that could lead to better control of impulsive aggression are of interest. METHODS: We analyzed the composition and diversity of the gut bacterial microbiome of 33 impulsively violent female convicts with dissocial personality disorder and 20 non-impulsive age-matched women. Further, levels of assorted neurotransmitters and short-chain fatty acids (SCFAs) were analyzed in serum and stool samples. We also assessed all participants using a battery of psychological questionnaires and tested possible correlations between the collected clinical data and the composition and diversity of their microbiomes and metabolites. RESULTS: We identified four bacterial amplicon sequencing variants that were differentially abundant in non-impulsive versus impulsive women - the genera Bacteroides, Barnesiella, and the order Rhodospirillales were more abundant in impulsive women. In contrast, the genus Catenisphaera was more abundant in non-impulsive women. Fecal tryptophan levels were significantly higher in impulsive women. Association analysis revealed a strong positive intercorrelation between most fecal SCFAs in the entire dataset. CONCLUSIONS: Our study demonstrated possible associations between gut microbiomes and their metabolites and impulsive behavior in a unique cohort of prisoners convicted of violent assaults and a matched group of non-impulsive women from the same prison. Genus Bacteroides, which was differentially abundant in the two groups, encoded enzymes that affect serotonin pathways and could contribute to this maladaptive behavior. Similarly, increased fecal tryptophan levels in impulsive individuals could affect neuronal circuits in the brain. INTRODUCTION: Impulsivity and aggression are often interlinked behavioral traits that have major implications for our society. Therefore, the study of this phenomenon and derivative interventions that could lead to better control of impulsive aggression are of interest. METHODS: We analyzed the composition and diversity of the gut bacterial microbiome of 33 impulsively violent female convicts with dissocial personality disorder and 20 non-impulsive age-matched women. Further, levels of assorted neurotransmitters and short-chain fatty acids (SCFAs) were analyzed in serum and stool samples. We also assessed all participants using a battery of psychological questionnaires and tested possible correlations between the collected clinical data and the composition and diversity of their microbiomes and metabolites. RESULTS: We identified four bacterial amplicon sequencing variants that were differentially abundant in non-impulsive versus impulsive women - the genera Bacteroides, Barnesiella, and the order Rhodospirillales were more abundant in impulsive women. In contrast, the genus Catenisphaera was more abundant in non-impulsive women. Fecal tryptophan levels were significantly higher in impulsive women. Association analysis revealed a strong positive intercorrelation between most fecal SCFAs in the entire dataset. CONCLUSIONS: Our study demonstrated possible associations between gut microbiomes and their metabolites and impulsive behavior in a unique cohort of prisoners convicted of violent assaults and a matched group of non-impulsive women from the same prison. Genus Bacteroides, which was differentially abundant in the two groups, encoded enzymes that affect serotonin pathways and could contribute to this maladaptive behavior. Similarly, increased fecal tryptophan levels in impulsive individuals could affect neuronal circuits in the brain.

• MeSH
• Aggression physiology   MeSH
• Adult MeSH
• Feces * microbiology   chemistry   MeSH
• Impulsive Behavior * physiology   MeSH
• Fatty Acids, Volatile analysis   metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Gastrointestinal Microbiome * physiology   MeSH
• Tryptophan blood   metabolism   MeSH
• Criminals MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

OBJECTIVES: To develop a gadolinium-free MRI-based diagnosis prediction decision tree (DPDT) for adult-type diffuse gliomas and to assess the added value of gadolinium-based contrast agent (GBCA) enhanced images. MATERIALS AND METHODS: This study included preoperative grade 2-4 adult-type diffuse gliomas (World Health Organization 2021) scanned between 2010 and 2021. The DPDT, incorporating eleven GBCA-free MRI features, was developed using 18% of the dataset based on consensus readings. Diagnosis predictions involved grade (grade 2 vs. grade 3/4) and molecular status (isocitrate dehydrogenase (IDH) and 1p/19q). GBCA-free diagnosis was predicted using DPDT, while GBCA-enhanced diagnosis included post-contrast images. The accuracy of these predictions was assessed by three raters with varying experience levels in neuroradiology using the test dataset. Agreement analyses were applied to evaluate the prediction performance/reproducibility. RESULTS: The test dataset included 303 patients (age (SD): 56.7 (14.2) years, female/male: 114/189, low-grade/high-grade: 54/249, IDH-mutant/wildtype: 82/221, 1p/19q-codeleted/intact: 34/269). Per-rater GBCA-free predictions achieved ≥ 0.85 (95%-CI: 0.80-0.88) accuracy for grade and ≥ 0.75 (95%-CI: 0.70-0.80) for molecular status, while GBCA-enhanced predictions reached ≥ 0.87 (95%-CI: 0.82-0.90) and ≥ 0.77 (95%-CI: 0.71-0.81), respectively. No accuracy difference was observed between GBCA-free and GBCA-enhanced predictions. Group inter-rater agreement was moderate for GBCA-free (0.56 (95%-CI: 0.46-0.66)) and substantial for GBCA-enhanced grade prediction (0.68 (95%-CI: 0.58-0.78), p = 0.008), while substantial for both GBCA-free (0.75 (95%-CI: 0.69-0.80) and GBCA-enhanced (0.77 (95%-CI: 0.71-0.82), p = 0.51) molecular status predictions. CONCLUSION: The proposed GBCA-free diagnosis prediction decision tree performed well, with GBCA-enhanced images adding little to the preoperative diagnostic accuracy of adult-type diffuse gliomas. KEY POINTS: Question Given health and environmental concerns, is there a gadolinium-free imaging protocol to preoperatively evaluate gliomas comparable to the gadolinium-enhanced standard practice? Findings The proposed gadolinium-free diagnosis prediction decision tree for adult-type diffuse gliomas performed well, and gadolinium-enhanced MRI demonstrated only limited improvement in diagnostic accuracy. Clinical relevance Even inexperienced raters effectively classified adult-type diffuse gliomas using the gadolinium-free diagnosis prediction decision tree, which, until further validation, can be used alongside gadolinium-enhanced images to respect standard practice, despite this study showing that gadolinium-enhanced images hardly improved diagnostic accuracy.

• MeSH
• Adult MeSH
• Gadolinium MeSH
• Glioma * diagnostic imaging   MeSH
• Contrast Media * MeSH
• Middle Aged MeSH
• Humans MeSH
• Magnetic Resonance Imaging * methods   MeSH
• Brain Neoplasms * diagnostic imaging   MeSH
• Predictive Value of Tests MeSH
• Reproducibility of Results MeSH
• Decision Trees * MeSH
• Aged MeSH
• Neoplasm Grading * MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Bipolar disorder (BD) is a complex and heterogeneous psychiatric disorder. It has been suggested that neurodevelopmental factors contribute to the etiology of BD, but a specific neurodevelopmental phenotype (NDP) of the disorder has not been identified. Our objective was to define and characterize an NDP in BD and validate its associations with clinical outcomes, polygenic risk scores, and treatment responses. METHODS: We analyzed the FondaMental Advanced Centers of Expertise for Bipolar Disorders cohort of 4468 patients with BD, a validation cohort of 101 patients with BD, and 2 independent replication datasets of 274 and 89 patients with BD. Using factor analyses, we identified a set of criteria for defining NDP. Next, we developed a scoring system for NDP load and assessed its association with prognosis, neurological soft signs, polygenic risk scores for neurodevelopmental disorders, and responses to treatment using multiple regressions, adjusted for age and gender with bootstrap replications. RESULTS: Our study established an NDP in BD consisting of 9 clinical features: advanced paternal age, advanced maternal age, childhood maltreatment, attention-deficit/hyperactivity disorder, early onset of BD, early onset of substance use disorders, early onset of anxiety disorders, early onset of eating disorders, and specific learning disorders. Patients with higher NDP load showed a worse prognosis and increased neurological soft signs. Notably, these individuals exhibited a poorer response to lithium treatment. Furthermore, a significant positive correlation was observed between NDP load and polygenic risk score for attention-deficit/hyperactivity disorder, suggesting potential overlapping genetic factors or pathophysiological mechanisms between BD and attention-deficit/hyperactivity disorder. CONCLUSIONS: The proposed NDP constitutes a promising clinical tool for patient stratification in BD.

• MeSH
• Bipolar Disorder * genetics   MeSH
• Adult MeSH
• Phenotype * MeSH
• Attention Deficit Disorder with Hyperactivity genetics   MeSH
• Cohort Studies MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Multifactorial Inheritance genetics   MeSH
• Neurodevelopmental Disorders genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

PURPOSE: Dual velocity encoding PC-MRI can produce spurious artifacts when using high ratios of velocity encoding values (VENCs), limiting its ability to generate high-quality images across a wide range of encoding velocities. This study aims to propose and compare dual-VENC correction methods for such artifacts. THEORY AND METHODS: Two denoising approaches based on spatiotemporal regularization are proposed and compared with a state-of-the-art method based on sign correction. Accuracy is assessed using simulated data from an aorta and brain aneurysm, as well as 8 two-dimensional (2D) PC-MRI ascending aorta datasets. Two temporal resolutions (30,60) ms and noise levels (9,12) dB are considered, with noise added to the complex magnetization. The error is evaluated with respect to the noise-free measurement in the synthetic case and to the unwrapped image without additional noise in the volunteer datasets. RESULTS: In all studied cases, the proposed methods are more accurate than the Sign Correction technique. Using simulated 2D+T data from the aorta (60 ms, 9 dB), the Dual-VENC (DV) error 0.82±0.07$$ 0.82\pm 0.07 $$ is reduced to: 0.66±0.04$$ 0.66\pm 0.04 $$ (Sign Correction); 0.34±0.04$$ 0.34\pm 0.04 $$ and 0.32±0.04$$ 0.32\pm 0.04 $$ (proposed techniques). The methods are found to be significantly different (p-value <0.05$$ <0.05 $$ ). Importantly, brain aneurysm data revealed that the Sign Correction method is not suitable, as it increases error when the flow is not unidirectional. All three methods improve the accuracy of in vivo data. CONCLUSION: The newly proposed methods outperform the Sign Correction method in improving dual-VENC PC-MRI images. Among them, the approach based on temporal differences has shown the highest accuracy.

• MeSH
• Algorithms * MeSH
• Aorta * diagnostic imaging   MeSH
• Artifacts * MeSH
• Phantoms, Imaging MeSH
• Image Interpretation, Computer-Assisted methods   MeSH
• Intracranial Aneurysm diagnostic imaging   MeSH
• Humans MeSH
• Magnetic Resonance Imaging * methods   MeSH
• Brain diagnostic imaging   MeSH
• Computer Simulation MeSH
• Image Processing, Computer-Assisted * methods   MeSH
• Signal-To-Noise Ratio * MeSH
• Reproducibility of Results MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

The honeybee (Apis mellifera) is a key pollinator critical to global agriculture, facing threats from various stressors, including the ectoparasitic Varroa mite (Varroa destructor). Previous studies have identified shared bacteria between Varroa mites and honeybees, yet it remains unclear if these bacteria assemble similarly in both species. This study builds on existing knowledge by investigating co-occurrence patterns in the microbiomes of both Varroa mites and honeybees, shedding light on potential interactions. Leveraging 16S rRNA datasets, we conducted co-occurrence network analyses, explored Core Association Networks (CAN) and assess network robustness. Comparative network analyses revealed structural differences between honeybee and mite microbiomes, along with shared core features and microbial motifs. The mite network exhibited lower robustness, suggesting less resistance to taxa extension compared to honeybees. Furthermore, analyses of predicted functional profiling and taxa contribution revealed that common central pathways in the metabolic networks have different taxa contributing to Varroa mites and honeybee microbiomes. The results show that while both microbial systems exhibit functional redundancy, in which different taxa contribute to the functional stability and resilience of the ecosystem, there is evidence for niche specialization resulting in unique contributions to specific pathways in each part of this host-parasite system. The specificity of taxa contribution to key pathways offers targeted approaches to Varroa microbiome management and preserving honeybee microbiome. Our findings provide valuable insights into microbial interactions, aiding farmers and beekeepers in maintaining healthy and resilient bee colonies amid increasing Varroa mite infestations.

• MeSH
• Bacteria * classification   genetics   isolation & purification   MeSH
• Microbiota * MeSH
• RNA, Ribosomal, 16S genetics   MeSH
• Varroidae * microbiology   MeSH
• Bees microbiology   parasitology   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH

The characteristics at diagnosis and clinical course of primary extranodal follicular lymphoma (EFL) have not been extensively described. The International Extranodal Lymphoma Study Group (IELSG) conducted an international retrospective survey aimed to describe the clinical features at diagnosis and the outcomes of FL cases with a clinically dominant extranodal component. The dataset included 605 pathologically reviewed cases from 19 different countries, and their outcomes were compared to those of nodal follicular lymphomas. The two most common presentation sites for EFL were the skin (n = 334) and the gastrointestinal tract (n = 72), with 22 cases having primary duodenal localization. These subsets exhibited unique features at diagnosis and significantly different overall survival (OS) patterns. After a median follow-up of 5.5 years, primary cutaneous lymphomas showed a superior outcome [10-year OS: 89% (95% CI, 83%-93%)], while primary gastrointestinal lymphomas had an intermediate outcome [10-year OS: 79% (95% CI, 59%-90%)]. Among the gastrointestinal lymphomas, primary duodenal lymphomas tended toward the best outcome [10-year OS: 95% (95% CI, 69%-99%)]. Other primary extranodal sites had inferior outcomes [10-year OS: 59% (95% CI, 48%-68%)], similar to primary nodal lymphomas [10-year OS: 57% (95% CI, 49%-64%)]. These findings support the identification of specific primary FL localizations as distinct entities with particular clinical and biological characteristics.

• MeSH
• Adult MeSH
• Lymphoma, Follicular * mortality   therapy   diagnosis   pathology   epidemiology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Survival Rate MeSH
• Young Adult MeSH
• Follow-Up Studies MeSH
• Prognosis MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH

BackgroundDuring the COVID-19 pandemic, non-pharmaceutical interventions (NPIs) such as social distancing, lockdowns and enhanced hygiene led to a decrease in respiratory pathogens. However, as NPIs were relaxed, a resurgence in several respiratory pathogens was observed including one local Chlamydia pneumoniae outbreak in Switzerland, prompting the need for a better understanding of C. pneumoniae epidemiology.AimTo assess temporal and geographical variations in C. pneumoniae detection before, during and after the COVID-19 pandemic.MethodsData on C. pneumoniae PCR detection ratios (number of positive tests/ total number of tests) across pre-pandemic (2018-2019), pandemic (2020-2022) and post-pandemic (2023) periods were collected via a global survey disseminated through various professional networks.ResultsC. pneumoniae detection ratios were analysed across 28 sites (27 in Europe, one in Taiwan) in 2023 (Dataset A, n = 172,223 tests) and 20 sites from 2018 to 2023 (Dataset B, n = 693,106 tests). Twenty-seven sites were laboratories (hospital or clinical) and one a surveillance system (Denmark). A significant decrease in detection ratios was observed during the pandemic period (from 1.05% to 0.23%, p < 0.001). In 2023, detection ratios increased to 0.28% (p < 0.002). Notable regional variations were found, with statistically significant increases in detection ratios at six sites located in Switzerland and Slovenia, where ratios ranged from 0.52% to 3.25%.DiscussionThe study highlights how NPIs influenced C. pneumoniae epidemiology, with reduced detection during the pandemic and partial resurgence afterwards. Regional variations suggest differing NPI impacts and underscore the need for continued surveillance.

• MeSH
• Chlamydophila pneumoniae * isolation & purification   genetics   MeSH
• COVID-19 * epidemiology   MeSH
• Chlamydophila Infections * epidemiology   diagnosis   MeSH
• Humans MeSH
• Pandemics MeSH
• Polymerase Chain Reaction MeSH
• SARS-CoV-2 MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Europe MeSH
• Taiwan MeSH