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Abstract Background NEK10, a serine/threonine/tyrosine kinase belonging to the NEK (NIMA-related kinases) family, has been associated with diverse cellular processes. However, no specific target pathways have been identified. Our previous work knocking down NEK10 in HeLa cells suggested a functional association with mitochondria, as we observed altered mitochondrial morphology, mitochondrial oxygen consumption, mtDNA integrity, and reactive oxygen species levels. Methods To better understand this association, we studied human HAP1 cells fully knockout for NEK10 and confirmed that NEK10 has an important role in mitochondrial homeostasis. We performed the study of mitochondrial respiration, mitochondrial morphology, mitochondrial mass, and mtDNA analysis. Additionally, we showed proteome and phosphoproteome data of crude mitochondrial fraction of Parental and NEK10 KO cells using liquid chromatography-mass spectrometry (LC–MS/MS). Results In the absence of NEK10 several mitochondrial functions were disturbed. Moreover, proteome and phosphoproteome analyses of mitochondrial fractions showed that NEK10 alters the threonine phosphorylation status of several mitochondrial/endoplasmic reticulum components, including HSP60, NDUFB4, and TOM20. These changes impacted the steady-state levels of a larger group of proteins, preferentially involving respiratory complexes and autophagy pathways. Conclusion We concluded that NEK10 plays a key role in mitochondrial function, possibly by modulating the phosphorylation status of mitochondrial proteins.

Abstract In this article we address two related issues on the learning of probabilistic sequences of events. First, which features make the sequence of events generated by a stochastic chain more difficult to predict. Second, how to model the procedures employed by different learners to identify the structure of sequences of events. Playing the role of a goalkeeper in a video game, participants were told to predict step by step the successive directions—left, center or right—to which the penalty kicker would send the ball. The sequence of kicks was driven by a stochastic chain with memory of variable length. Results showed that at least three features play a role in the first issue: (1) the shape of the context tree summarizing the dependencies between present and past directions; (2) the entropy of the stochastic chain used to generate the sequences of events; (3) the existence or not of a deterministic periodic sequence underlying the sequences of events. Moreover, evidence suggests that best learners rely less on their own past choices to identify the structure of the sequences of events.

Abstract Acting as a goalkeeper in a video-game, a participant is asked to predict the successive choices of the penalty taker. The sequence of choices of the penalty taker is generated by a stochastic chain with memory of variable length. It has been conjectured that the probability distribution of the response times is a function of the specific sequence of past choices governing the algorithm used by the penalty taker to make his choice at each step. We found empirical evidence that besides this dependence, the distribution of the response times depends also on the success or failure of the previous prediction made by the participant. Moreover, we found statistical evidence that this dependence propagates up to two steps forward after the prediction failure.

Abstract Clinical research relies on high-quality patient data, however, obtaining big data sets is costly and access to existing data is often hindered by privacy and regulatory concerns. Synthetic data generation holds the promise of effectively bypassing these boundaries allowing for simplified data accessibility and the prospect of synthetic control cohorts. We employed two different methodologies of generative artificial intelligence – CTAB-GAN+ and normalizing flows (NFlow) – to synthesize patient data derived from 1606 patients with acute myeloid leukemia, a heterogeneous hematological malignancy, that were treated within four multicenter clinical trials. Both generative models accurately captured distributions of demographic, laboratory, molecular and cytogenetic variables, as well as patient outcomes yielding high performance scores regarding fidelity and usability of both synthetic cohorts (n = 1606 each). Survival analysis demonstrated close resemblance of survival curves between original and synthetic cohorts. Inter-variable relationships were preserved in univariable outcome analysis enabling explorative analysis in our synthetic data. Additionally, training sample privacy is safeguarded mitigating possible patient re-identification, which we quantified using Hamming distances. We provide not only a proof-of-concept for synthetic data generation in multimodal clinical data for rare diseases, but also full public access to synthetic data sets to foster further research.

ABSTRACT: Salmonella Reading (S. Reading) recently emerged as a foodborne pathogen causing extensive human outbreaks in North America from consuming contaminated poultry products, mostly from turkeys. Understanding the transmission dynamics of this pathogen is crucial for preventing future outbreaks. This study investigated the ability of S. Reading to colonize the tissues and contaminate eggs of broiler breeders. We utilized 2 S. Reading strains, marked with bioluminescence gene: the outbreak strain RS330 and a reference strain RS326. We used 32 commercially sourced broiler breeder hens, 34 wk of age, randomly assigned to the 2 treatments (16 hens per strain). Each hen was intravaginally inoculated with 108 CFU of the respective strain on d 1 and was rechallenged on d 4. Eggs were collected daily postchallenge to recover bioluminescent S. Reading strains from the external eggshell surface and internal egg contents. On d 7 postchallenge, 10 hens from each treatment group were euthanized. Ovaries, oviducts, and ceca were aseptically collected to detect S. Reading colonization. Results showed that 70.5% (36 of 51) and 34.5% (19 of 55) of external eggshell surfaces, and 4.0% (2 of 50) and 1.8% (1 of 54) of the internal egg contents tested positive for the outbreak and nonoutbreak strains. Additionally, 40.0% of ovaries, 70.0% of oviduct, and 70.0% of ceca samples from the outbreak strain group, and 20.0% of ovaries, 70.0% of oviduct, and 80.0% of ceca samples from nonoutbreak strain group were positive. No significant difference (P = 0.05) was observed in all the findings among the strains except for the eggshell surface contamination. These findings suggest that S. Reading can effectively colonize reproductive tissues, translocate to the ceca, and contaminate the eggs of hens. Future research is needed to determine whether S. Reading can remain viable within the eggs throughout incubation and until hatching.

Background: This prospective study investigates the pattern of pareses in 5q-associated spinal muscular atrophy (SMA) to identify disease-specific characteristics and potential differences from amyotrophic lateral sclerosis (ALS) and spinobulbar muscular atrophy (SBMA). Detailed knowledge about pareses patterns in SMA facilitates differential diagnosis and supports therapeutic monitoring. Methods: Between January 2021, and June 2021, 66 SMA patients (59.1% male, aged 33.6 ± 15.2 years) were included in the study. Most patients had SMA type II ( n = 28) or SMA type III ( n = 28), seven patients had SMA type I, and three patients had SMA type IV. We analyzed the pattern of pareses using the UK Medical Research Council (MRC) scoring system. Results: In both, upper and lower limbs muscle weakness was less pronounced in distal (upper limbs: MRC median 3.0 (interquartile range 1.5–3.5); lower limbs: 1.5 (0.5–3.0)) compared to proximal muscle groups (upper limbs: 2.0 (1.5–2.6); p

Postoperative delirium (POD) contributes to severe outcomes such as death or development of dementia. Thus, it is desirable to identify vulnerable patients in advance during the perioperative phase. Previous studies mainly investigated risk factors for delirium during hospitalization and further used a linear logistic regression (LR) approach with time-invariant data. Studies have not investigated patients' fluctuating conditions to support POD precautions. In this single-center study, we aimed to predict POD in a recovery room setting with a non-linear machine learning (ML) technique using pre-, intra-, and postoperative data. The target variable POD was defined with the Nursing Screening Delirium Scale (Nu-DESC) ≥ 1. Feature selection was conducted based on robust univariate test statistics and L1 regularization. Non-linear multi-layer perceptron (MLP) as well as tree-based models were trained and evaluated-with the receiver operating characteristics curve (AUROC), the area under precision recall curve (AUPRC), and additional metrics-against LR and published models on bootstrapped testing data. The prevalence of POD was 8.2% in a sample of 73,181 surgeries performed between 2017 and 2020. Significant univariate impact factors were the preoperative ASA status (American Society of Anesthesiologists physical status classification system), the intraoperative amount of given remifentanil, and the postoperative Aldrete score. The best model used pre-, intra-, and postoperative data. The non-linear boosted trees model achieved a mean AUROC of 0.854 and a mean AUPRC of 0.418 outperforming linear LR, well as best applied and retrained baseline models. Overall, non-linear machine learning models using data from multiple perioperative time phases were superior to traditional ones in predicting POD in the recovery room. Class imbalance was seen as a main impediment for model application in clinical practice.

Invertebrates use the endoribonuclease Dicer to cleave viral dsRNA during antiviral defense, while vertebrates use RIG-I-like Receptors (RLRs), which bind viral dsRNA to trigger an interferon response. While some invertebrate Dicers act alone during antiviral defense, Caenorhabditis elegans Dicer acts in a complex with a dsRNA binding protein called RDE-4, and an RLR ortholog called DRH-1. We used biochemical and structural techniques to provide mechanistic insight into how these proteins function together. We found RDE-4 is important for ATP-independent and ATP-dependent cleavage reactions, while helicase domains of both DCR-1 and DRH-1 contribute to ATP-dependent cleavage. DRH-1 plays the dominant role in ATP hydrolysis, and like mammalian RLRs, has an N-terminal domain that functions in autoinhibition. A cryo-EM structure indicates DRH-1 interacts with DCR-1’s helicase domain, suggesting this interaction relieves autoinhibition. Our study unravels the mechanistic basis of the collaboration between two helicases from typically distinct innate immune defense pathways.

In newly diagnosed acute myeloid leukemia, immediate initiation of treatment is standard of care. However, deferral of antileukemic therapy may be indicated to assess comorbidities or pre-therapeutic risk factors. We explored the impact of time from diagnosis to treatment on outcomes in newly diagnosed acute myeloid leukemia undergoing venetoclax-based therapy in two distinct cohorts. By querying the Study Alliance Leukemia database and the global health network TriNetX, we identified 138 and 717 patients respectively with an average age of 76 and 72 years who received venetoclax-based firstline therapy. When comparing patients who started treatment earlier or later than 10 days after initial diagnosis, no significant difference in median overall survival was observed - neither in the SAL cohort (7.7 vs. 9.6 months, p=.42) nor in the TriNetX cohort (7.5 vs. 7.2 months, p=.41). Similarly, severe infections, bleeding, and thromboembolic events were equally observed between early and later treatments, both in the overall patient groups and specific subgroups (age ≥75 years or leukocytes ≥20x109/L). This retrospective analysis indicates that delaying the start of venetoclax-based therapy in newly diagnosed acute myeloid leukemia might be a safe option for selected patients, provided that close clinical monitoring is performed.

Abstract Cannabis, the most prevalent drug in Latin America, has long been associated with the state of Sinaloa, Mexico, known for its cultivation and distribution. Despite increasing global acceptance, cannabis use remains stigmatized in Mexican society, driven by perceptions of it as a highly psychoactive and addictive substance lacking medicinal or industrial value. This study investigates the impact of scientific information on societal perceptions of cannabis in Sinaloa. A large convenience sample of 3162 individuals from Sinaloa participated in this research, responding to a questionnaire on cannabis consumption and attitudes. Participants were then subjected to an intervention consisting of an informative briefing based on the documents “Using Evidence to Talk About Cannabis” and “State of the Evidence: cannabis use and regulation" by the International Centre for Science in Drug Policy. After the intervention, participants' attitudes were immediately reevaluated through the same questionnaire, allowing for a comparison of pre- and post-intervention responses. The results indicate that the intervention (providing scientific information) significantly influenced attitudes toward cannabis, with education and age playing prominent roles in its effectiveness. Notably, the intervention fostered more positive or more neutral attitudes, potentially reducing stigma and promoting a better-informed perspective on cannabis. This study highlights the pivotal role of evidence in shaping informed citizens' views, while underscoring the importance of countering misinformation for societal progress. These findings have significant implications for forthcoming cannabis policy modifications in Mexico, emphasizing the necessity of engaging knowledgeable individuals in policy decisions to address the violence and inequalities associated with the illicit drug trade, particularly in Sinaloa.

Zika virus (ZIKV), a re-emerging flavivirus, is associated with devasting developmental and neurological disease outcomes particularly in infants infected in utero. Towards understanding the molecular underpinnings of the unique ZIKV disease pathologies, numerous transcriptome-wide studies have been undertaken. Notably, these studies have overlooked the assimilation of RNA-seq analysis from ZIKV-infected patients with cell culture model systems. In this study we find that ZIKV-infection of human lung adenocarcinoma A549 cells, mirrored both the transcriptional and alternative splicing profiles from previously published RNA-seq data of peripheral blood mononuclear cells collected from pediatric patients during early acute, late acute, and convalescent phases of ZIKV infection. Our analyses show that ZIKV infection in cultured cells correlates with transcriptional changes in patients, while the overlap in alternative splicing profiles was not as extensive. Overall, our data indicate that cell culture model systems support dissection of select molecular changes detected in patients and establishes the groundwork for future studies elucidating the biological implications of alternative splicing during ZIKV infection.

Abstract A growing body of literature suggests the important role of the thalamus in cognition and neurodegenerative diseases. This study aims to elucidate whether the preoperative thalamic volume is associated with preoperative cognitive impairment (preCI) and whether it is predictive for postoperative cognitive dysfunction at 3 months (POCD). We enrolled 301 patients aged 65 or older and without signs of dementia who were undergoing elective surgery. Magnetic resonance imaging was conducted prior to surgery. Freesurfer (version 5.3.) was used to automatically segment the thalamus volume. A neuropsychological test battery was administered before surgery and at a 3 month follow-up. It included the computerized tests Paired Associate Learning (PAL), Verbal Recognition Memory (VRM), Spatial Span Length (SSP), Simple Reaction Time (SRT), the pen-and-paper Trail-Making-Test (TMT) and the manual Grooved Pegboard Test (GPT). Using a reliable change index, preCI and POCD were defined as total Z-score > 1.96 (sum score over all tests) and/or Z-scores > 1.96 in ≥ 2 individual cognitive test parameters. For statistical analyses, multivariable logistic regression models were applied. Age, sex and intracranial volume were covariates in the models. Of 301 patients who received a presurgical neuropsychological testing and MRI, 34 (11.3%) had preCI. 89 patients (29.5%) were lost to follow-up. The remaining 212 patients received a follow-up cognitive test after 3 months, of whom 25 (8.3%) presented with POCD. Independently of age, sex and intracranial volume, neither preCI (OR per cm3 increment 0.81 [95% CI 0.60–1.07] p = 0.14) nor POCD (OR 1.02 per cm3 increment [95% CI 0.75–1.40] p = 0.87) were statistically significantly associated with patients’ preoperative thalamus volume. In this cohort we could not show an association of presurgical thalamus volume with preCI or POCD. Clinical Trial Number: NCT02265263 ( https://clinicaltrials.gov/ct2/show/results/NCT02265263 ).

Background: The Trail Making Test B (TMT-B) is indicative of cognitive flexibility and several other cognitive domains. Previous studies suggest that it might be associated with the risk of developing postoperative delirium, but evidence is limited and conflicting. We therefore aimed to replicate the association of preoperative TMT-B results with postoperative delirium. Methods: We included older adults (≥65 yr) scheduled for major surgery and without signs of dementia to participate in this binational two-centre longitudinal observational cohort study. Presurgical TMT-B scores were obtained. Delirium was assessed twice daily using validated instruments. Logistic regression was applied and the area under the receiver operating characteristic curve calculated to determine the predictive performance of TMT-B. We subsequently included covariates used in previous studies for consecutive sensitivity analyses. We further analysed the impact of outliers, missing or impaired data. Results: Data from 841 patients were included and of those, 151 (18%) developed postoperative delirium. TMT-B scores were statistically significantly associated with the incidence of postoperative delirium {odds ratio per 10-s increment 1.06 (95% confidence interval [CI] 1.02–1.09), P=0.001}. The area under the receiver operating characteristic curve was 0.60 ([95% CI 0.55–0.64], P

Background/ObjectiveNeurofilament light chain (NfL) has been proposed as a biomarker reflecting disease severity and therapy response in children with spinal muscular atrophy type 1 and 2 (SMA1 and 2). The objective of this study was to examine how serum NfL changes after gene replacement therapy (GRT) with onasemnogene abeparvovec-xioi.MethodsWe measured NfL in serum probes from 19 patients (10 SMA 1 and 6 SMA 2; 15 previously treated with nusinersen or risdiplam; 12 male) before and at variable time points after GRT. These values were related to motor scores (CHOP-Intend, HFMSE and RULM).ResultsMedian age at GRT was 19 months (range 2–46 months). Median NfL of all patients before GRT was 39 pg/ml (range 0–663 pg/ml; normal values

Summary: Background: There is an urgent need to better understand and prevent relapse in major depressive disorder (MDD). We explored the differential impact of various MDD relapse prevention strategies (pharmacological and/or psychological) on affect fluctuations and individual affect networks in a randomised setting, and their predictive value for relapse. Methods: We did a secondary analysis using experience sampling methodology (ESM) data from individuals with remitted recurrent depression that was collected alongside a randomised controlled trial that ran in the Netherlands, comparing: (I) tapering antidepressants while receiving preventive cognitive therapy (PCT), (II) combining antidepressants with PCT, or (III) continuing antidepressants without PCT, for the prevention of depressive relapse, as well as ESM data from 11 healthy controls. Participants had multiple past depressive episodes, but were remitted for at least 8 weeks and on antidepressants for at least six months. Exclusion criteria were: current (hypo)mania, current alcohol or drug abuse, anxiety disorder that required treatment, psychological treatment more than twice per month, a diagnosis of organic brain damage, or a history of bipolar disorder or psychosis. Fluctuations (within-person variance, root mean square of successive differences, autocorrelation) in negative and positive affect were calculated. Changes in individual affect networks during treatment were modelled using time-varying vector autoregression, both with and without applying regularisation. We explored whether affect fluctuations or changes in affect networks over time differed between treatment conditions or relapse outcomes, and predicted relapse during 2-year follow-up. This ESM study was registered at ISRCTN registry, ISRCTN15472145. Findings: Between Jan 1, 2014, and Jan 31, 2015, 72 study participants were recruited, 42 of whom were included in the analyses. We found no indication that affect fluctuations differed between treatment groups, nor that they predicted relapse. We observed large individual differences in affect network structure across participants (irrespective of treatment or relapse status) and in healthy controls. We found no indication of group-level differences in how much networks changed over time, nor that changes in networks over time predicted time to relapse (regularised models: hazard ratios [HR] 1063, 95% CI 10 000, p = 0.65; non-regularised models: HR 2.54, 95% CI 0.23–28.7, p = 0.45) or occurrence of relapse (regularised models: odds ratios [OR] 22.84, 95% CI 10 000, p = 0.90; non-regularised models: OR 7.57, 95% CI 0.07–3709.54, p = 0.44) during complete follow-up. Interpretation: Our findings should be interpreted with caution, given the exploratory nature of this study and wide confidence intervals. While group-level differences in affect dynamics cannot be ruled out due to low statistical power, visual inspection of individual affect networks also revealed no meaningful patterns in relation to MDD relapse. More studies are needed to assess whether affect dynamics as informed by ESM may predict relapse or guide personalisation of MDD relapse prevention in daily practice. Funding: The Netherlands Organisation for Health Research and Development, Dutch Research Council, University of Amsterdam.

Abstract Tandem-duplication mutations of the UBTF gene (UBTF-TDs) coding for the upstream binding transcription factor have recently been described in pediatric patients with acute myeloid leukemia (AML) and were found to be associated with particular genetics (trisomy 8 (+8), FLT3-internal tandem duplications (FLT3-ITD), WT1-mutations) and inferior outcome. Due to limited knowledge on UBTF-TDs in adult AML, we screened 4247 newly diagnosed adult AML and higher-risk myelodysplastic syndrome (MDS) patients using high-resolution fragment analysis. UBTF-TDs were overall rare (n = 52/4247; 1.2%), but significantly enriched in younger patients (median age 41 years) and associated with MDS-related morphology as well as significantly lower hemoglobin and platelet levels. Patients with UBTF-TDs had significantly higher rates of +8 (34% vs. 9%), WT1 (52% vs. 7%) and FLT3-ITD (50% vs. 20.8%) co-mutations, whereas UBTF-TDs were mutually exclusive with several class-defining lesions such as mutant NPM1, in-frame CEBPA bZIP mutations as well as t(8;21). Based on the high-variant allele frequency found and the fact that all relapsed patients analyzed (n = 5) retained the UBTF-TD mutation, UBTF-TDs represent early clonal events and are stable over the disease course. In univariate analysis, UBTF-TDs did not represent a significant factor for overall or relapse-free survival in the entire cohort. However, in patients under 50 years of age, who represent the majority of UBTF-mutant patients, UBTF-TDs were an independent prognostic factor for inferior event-free (EFS), relapse-free (RFS) and overall survival (OS), which was confirmed by multivariable analyses including established risk factors such as age and ELN2022 genetic risk groups (EFS [HR: 2.20; 95% CI 1.52–3.17, p

Abstract Background Increasingly large and complex biomedical data sets challenge conventional hypothesis-driven analytical approaches, however, data-driven unsupervised learning can detect inherent patterns in such data sets. Methods While unsupervised analysis in the medical literature commonly only utilizes a single clustering algorithm for a given data set, we developed a large-scale model with 605 different combinations of target dimensionalities as well as transformation and clustering algorithms and subsequent meta-clustering of individual results. With this model, we investigated a large cohort of 1383 patients from 59 centers in Germany with newly diagnosed acute myeloid leukemia for whom 212 clinical, laboratory, cytogenetic and molecular genetic parameters were available. Results Unsupervised learning identifies four distinct patient clusters, and statistical analysis shows significant differences in rate of complete remissions, event-free, relapse-free and overall survival between the four clusters. In comparison to the standard-of-care hypothesis-driven European Leukemia Net (ELN2017) risk stratification model, we find all three ELN2017 risk categories being represented in all four clusters in varying proportions indicating unappreciated complexity of AML biology in current established risk stratification models. Further, by using assigned clusters as labels we subsequently train a supervised model to validate cluster assignments on a large external multicenter cohort of 664 intensively treated AML patients. Conclusions Dynamic data-driven models are likely more suitable for risk stratification in the context of increasingly complex medical data than rigid hypothesis-driven models to allow for a more personalized treatment allocation and gain novel insights into disease biology.

Abstract Background Hemolysis is associated with increased mortality in patients with sepsis, ARDS, or therapy with extracorporeal membrane oxygenation (ECMO). To quantify a critical threshold of hemolysis in patients with ARDS and treatment with veno-venous ECMO, we aimed to identify cutoff values for cell-free hemoglobin (CFH) and haptoglobin (Hp) plasma concentrations associated with a significant increase in ICU mortality. Methods Patients with ARDS admitted to a tertiary ARDS referral center between 01/2007 and 12/2018 and treatment with veno-venous ECMO were included. Cutoff values for mean CFH (mCFH) and mean Hp (mHp) plasma concentrations dividing the cohort into groups with significantly different ICU mortalities were calculated and patient characteristics were compared. A multiple logistic regression model with stepwise backward variable selection was included. In addition, cutoff values for vulnerable relative timespans for the respective CFH and Hp concentrations were calculated. Results A quantitative cutoff value of 11 mg/dl for mCFH separated the cohort (n = 442) regarding ICU mortality (mCFH ≤ 11 mg/dl: 38%, [95%-CI: 32.22–43.93] (n = 277) vs. mCFH > 11 mg/dl: 70%, [61.99–76.47] (n = 165), p 0.39 g/l: 38.7%, [33.01–44.72] (n = 279), p 11 mg/dl: 33%; [26.81–40.54] (n = 192) vs. > 13.3% of days with CFH > 11 mg/dl: 62%; [56.05–68.36] (n = 250), p 18.2% of therapy days (≤ 18.2% days with Hp ≤ 0.39 g/l: 27%; [19.80–35.14] (n = 138) vs. > 18.2% days with Hp ≤ 0.39 g/l: 60%; [54.43–65.70] (n = 304), p 11 mg/dl. In addition, also Hp plasma concentrations need consideration when the injurious effect of elevated CFH is evaluated.

Melanocytes can de-differentiate into neural crest cell (NCC)- like states during metastatic melanoma progression. Here the authors compare DNA methylation profiles of NCCs and melanocytes, as well as primary and metastatic patient tissues and identify that DNA methylation changes of NR2F2 isoform 2 influence cell state transitions and melanoma metastatic spread.

The relationship between sleep, glial cells, and the endocannabinoid system represents a multifaceted regulatory network with profound implications for neuroinflammation and cognitive function. The molecular underpinnings of sleep modulation by the endocannabinoid system and its influence on glial cell activity are discussed, shedding light on the reciprocal relationships that govern these processes. Emphasis is placed on understanding the role of glial cells in mediating neuroinflammatory responses and their modulation by sleep patterns. Additionally, this review examines how the endocannabinoid system interfaces with glia-immune signaling to regulate inflammatory cascades within the central nervous system. Notably, the cognitive consequences of disrupted sleep, neuroinflammation, and glial dysfunction are addressed, encompassing implications for neurodegenerative disorders, mood disturbances, and cognitive decline. Insights into the bidirectional modulation of cognitive function by the endocannabinoid system in the context of sleep and glial activity are explored, providing a comprehensive perspective on the potential mechanisms underlying cognitive impairments associated with sleep disturbances. Furthermore, this review examines potential therapeutic avenues targeting the endocannabinoid system to mitigate neuroinflammation, restore glial homeostasis, and normalize sleep patterns. The identification of novel therapeutic targets within this intricate regulatory network holds promise for addressing conditions characterized by disrupted sleep, neuroinflammation, and cognitive dysfunction. This work aims to examine the complexities of neural regulation and identify potential avenues for therapeutic intervention.

Background & Aims: The nuclear receptor farnesoid X receptor (FXR) is a key regulator of hepatic bile acid (BA) and lipid metabolism, inflammation and fibrosis. Here, we aimed to explore the potential of cilofexor (GS-9674), a non-steroidal FXR agonist, as a therapeutic approach for counteracting features of cholestatic liver injury by evaluating its efficacy and mechanisms in the Mdr2/Abcb4 knockout (-/-) mouse model of sclerosing cholangitis. Methods: FVB/N wild-type and Mdr2-/- or BALB/c wild-type and Mdr2-/- mice were treated with 0, 10, 30 or 90 mg/kg cilofexor by gavage every 24 h for 10 weeks. Serum biochemistry, gene expression profile, hydroxyproline content, and picrosirius red and F4/80 immunostaining, were investigated. Bile flow, biliary bicarbonate and BA output, and hepatic BA profile, were assessed. Results: Cilofexor treatment improved serum levels of aspartate aminotransferase, alkaline phosphatase as well as BAs in Mdr2-/- animals. Hepatic fibrosis was improved, as reflected by the reduced picrosirius red-positive area and hydroxyproline content in liver sections of cilofexor-treated Mdr2-/- mice. Intrahepatic BA concentrations were lowered in cilofexor-treated Mdr2-/- mice, while hepatobiliary bile flow and bicarbonate output were increased. Conclusion: Collectively the current data show that cilofexor treatment improves cholestatic liver injury and decreases hepatic fibrosis in the Mdr2-/- mouse model of sclerosing cholangitis. Impact and implications: Treatment with cilofexor, a non-steroidal farnesoid X receptor (FXR) agonist, improved histological features of sclerosing cholangitis, cholestasis and hepatic fibrosis in the Mdr2-/- mouse model. These findings indicate, that pharmacological stimulation of intestinal FXR-mediated gut-liver signaling, via fibroblast growth factor 15 (thereby reducing bile acid synthesis), may be sufficient to attenuate cholestatic liver injury in the Mdr2-/- mouse model of sclerosing cholangitis, thus arguing for potential therapeutic properties of cilofexor in cholestatic liver diseases.

Current classifications (World Health Organization-HAEM5/ICC) define up to 26 molecular B-cell precursor acute lymphoblastic leukemia (BCP-ALL) disease subtypes by genomic driver aberrations and corresponding gene expression signatures. Identification of driver aberrations by transcriptome sequencing (RNA-Seq) is well established, while systematic approaches for gene expression analysis are less advanced. Therefore, we developed ALLCatchR, a machine learning-based classifier using RNA-Seq gene expression data to allocate BCP-ALL samples to all 21 gene expression-defined molecular subtypes. Trained on n = 1869 transcriptome profiles with established subtype definitions (4 cohorts; 55% pediatric / 45% adult), ALLCatchR allowed subtype allocation in 3 independent hold-out cohorts (n = 1018; 75% pediatric / 25% adult) with 95.7% accuracy (averaged sensitivity across subtypes: 91.1% / specificity: 99.8%). High-confidence predictions were achieved in 83.7% of samples with 98.9% accuracy. Only 1.2% of samples remained unclassified. ALLCatchR outperformed existing tools and identified novel driver candidates in previously unassigned samples. Additional modules provided predictions of samples blast counts, patient’s sex, and immunophenotype, allowing the imputation in cases where these information are missing. We established a novel RNA-Seq reference of human B-lymphopoiesis using 7 FACS-sorted progenitor stages from healthy bone marrow donors. Implementation in ALLCatchR enabled projection of BCP-ALL samples to this trajectory. This identified shared proximity patterns of BCP-ALL subtypes to normal lymphopoiesis stages, extending immunophenotypic classifications with a novel framework for developmental comparisons of BCP-ALL. ALLCatchR enables RNA-Seq routine application for BCP-ALL diagnostics with systematic gene expression analysis for accurate subtype allocation and novel insights into underlying developmental trajectories.

Abstract Background Many physicians do not know how to accurately interpret test results using Bayes’ rule. As a remedy, two kinds of interventions have been shown effective: boosting insight and boosting agency with natural frequencies. To boost insight, test statistics are provided in natural frequencies (rather than conditional probabilities), without instructions on how to use them. To boost agency, a training is provided on how to translate probabilities into natural frequencies and apply them in Bayes’ rule. What has not been shown is whether boosting agency is sufficient or if representing test statistics in natural frequencies may additionally boost insight to maximize accurate test interpretation. Methods We used a pre/posttest design to assess test interpretation accuracy of 577 medical students before and after a training on two Bayesian reasoning tasks, one providing conditional probabilities, the other natural frequencies. The pretest assessed baseline abilities versus the effect of natural frequencies to boost insight. After participants received a training on how to translate conditional probabilities into natural frequencies and how to apply them in Bayes’ rule, test interpretation skills were assessed using the same tasks again, comparing the effects of training-induced agency with versus without additionally boosting insight (i.e., test statistics in natural frequencies versus conditional probabilities). Results Compared to the test question formatted in conditional probabilities (34% correct answers), natural frequencies facilitated Bayesian reasoning without training (68%), that is, they increased insight. The training on how to use natural frequencies improved performance for tasks formatted in conditional probabilities (64%). Performance was maximal after training and with test statistics formatted in natural frequencies, that is, with a combination of boosting insight and agency (89%). Conclusions Natural frequencies should be used to boost insight and agency to maximize effective use of teaching resources. Thus, mandating that test statistics are provided in natural frequencies and adopting short trainings on how to translate conditional probabilities into natural frequencies and how to apply them in Bayes’ rule will help to maximize accurate test interpretation. Trial registration The study was a registered with the German Clinical Trial Registry ( DRKS00008723 ; 06/03/2015).

Background & Aims: Glucagon-like peptide (GLP)-2 may exert antifibrotic effects on hepatic stellate cells (HSCs). Thus, we aimed to test whether application of the GLP-2 analogue teduglutide has hepatoprotective and antifibrotic effects in the Mdr2/Abcb4-/- mouse model of sclerosing cholangitis displaying hepatic inflammation and fibrosis. Methods: Mdr2-/- mice were injected daily for 4 weeks with teduglutide followed by gene expression profiling (bulk liver; isolated HSCs) and immunohistochemistry. Activated HSCs (LX2 cells) and immortalized human hepatocytes and human intestinal organoids were treated with GLP-2. mRNA profiling by reverse transcription polymerase chain reaction and electrophoretic mobility shift assay using cytosolic and nuclear protein extracts was performed. Results: Hepatic inflammation, fibrosis, and reactive cholangiocyte phenotype were improved in GLP-2-treated Mdr2-/- mice. Primary HSCs isolated from Mdr2-/- mice and LX2 cells exposed to GLP-2 in vitro displayed significantly increased mRNA expression levels of NR4a1/Nur77 (P < .05). Electrophoretic mobility shift assay revealed an increased nuclear NR4a1 binding after GLP-2 treatment in LX2 cells. Moreover, GLP-2 alleviated the Tgfβ-mediated reduction of NR4a1 nuclear binding activity. In vivo, GLP-2 treatment of Mdr2-/- mice resulted in increased intrahepatic levels of muricholic acids (accordingly Cyp2c70 mRNA expression was significantly increased), and in reduced mRNA levels of Cyp7a1 and FXR. Serum Fgf15 levels were increased in Mdr2-/- mice treated with GLP-2. Accordingly, GLP-2 treatment of human intestinal organoids activated their FXR-FGF19 signaling axis. Conclusions: GLP-2 treatment increased NR4a1/Nur77 activation in HSCs, subsequently attenuating their activation. GLP-2 promoted intestinal Fxr-Fgf15/19 signaling resulting in reduced Cyp7a1 and increased Cyp2c70 expression in the liver, contributing to hepatoprotective and antifibrotic effects of GLP-2 in the Mdr2-/- mouse model.

Abstract Functional perturbations of the cohesin complex with subsequent changes in chromatin structure and replication are reported in a multitude of cancers including acute myeloid leukemia (AML). Mutations of its STAG2 subunit may predict unfavorable risk as recognized by the 2022 European Leukemia Net recommendations, but the underlying evidence is limited by small sample sizes and conflicting observations regarding clinical outcomes, as well as scarce information on other cohesion complex subunits. We retrospectively analyzed data from a multi-center cohort of 1615 intensively treated AML patients and identified distinct co-mutational patters for mutations of STAG2, which were associated with normal karyotypes (NK) and concomitant mutations in IDH2, RUNX1, BCOR, ASXL1, and SRSF2. Mutated RAD21 was associated with NK, mutated EZH2, KRAS, CBL, and NPM1. Patients harboring mutated STAG2 were older and presented with decreased white blood cell, bone marrow and peripheral blood blast counts. Overall, neither mutated STAG2, RAD21, SMC1A nor SMC3 displayed any significant, independent effect on clinical outcomes defined as complete remission, event-free, relapse-free or overall survival. However, we found almost complete mutual exclusivity of genetic alterations of individual cohesin subunits. This mutual exclusivity may be the basis for therapeutic strategies via synthetic lethality in cohesin mutated AML.

Abstract FAT atypical cadherin 1 (FAT1), a transmembrane protein, is frequently mutated in various cancer types and has been described as context-dependent tumor suppressor or oncogene. The FAT1 gene is mutated in 12–16% of T-cell acute leukemia (T-ALL) and aberrantly expressed in about 54% of T-ALL cases contrasted with absent expression in normal T-cells. Here, we characterized FAT1 expression and profiled the methylation status from T-ALL patients. In our T-ALL cohort, 53% of patient samples were FAT1 positive (FAT1pos) compared to only 16% FAT1 positivity in early T-ALL patient samples. Aberrant expression of FAT1 was strongly associated with FAT1 promotor hypomethylation, yet a subset, mainly consisting of TLX1-driven T-ALL patient samples showed methylation-independent high FAT1 expression. Genes correlating with FAT1 expression revealed enrichment in WNT signaling genes representing the most enriched single pathway. FAT1 knockdown or knockout led to impaired proliferation and downregulation of WNT pathway target genes (CCND1, MYC, LEF1), while FAT1 overexpressing conveyed a proliferative advantage. To conclude, we characterized a subtype pattern of FAT1 gene expression in adult T-ALL patients correlating with promotor methylation status. FAT1 dependent proliferation and WNT signaling discloses an impact on deeper understanding of T-ALL leukemogenesis as a fundament for prospective therapeutic strategies.

Abstract Background Postoperative delirium (POD) is a frequent complication after surgery. Older adult patients undergoing abdominal surgery are at higher risk for developing POD. Studies on the association of cholinesterase activities and POD are rare, but leading hypotheses implicate that the cholinergic pathway might play an important role in neuroinflammation and development of POD. The objective of this study was to figure out if there is an association between the development of POD and acetyl- and butyrylcholinesterase (AChE and BuChE) activities in older adult patients undergoing abdominal surgery. Methods The investigation was performed with a subpopulation of BioCog study patients. The BioCog project ( http://www.biocog.eu ) is a prospective multicenter observational study in older adult surgical patients. Patients ≥ 65 years undergoing elective surgery of at least 60 minutes who scored more than 23 points in the Mini-Mental-State-Examination were included. POD was assessed twice a day on seven consecutive days after the surgery, using the test instruments Nursing Delirium Screening Scale (Nu-Desc) and Confusion Assessment Method (CAM and CAM-ICU) and a patient chart review. Pre- and postoperative blood cholinesterase activities were measured with a photometric rapid-point-of-care-testing. The association between cholinesterase activities and POD was analyzed in a subpopulation of abdominal surgical patients using multivariable logistic regression analysis adjusting for confounders. Results One hundred twenty-seven patients were included for analysis (mean age 73 years, 59% female). Fifty-two patients (41%) fulfilled the criteria of POD. These patients were significantly older, had a longer time of surgery and anesthesia and achieved higher comorbidity scores compared to patients without POD. After adjusting for age, duration of surgery and charlson comorbity index, we found an association between pre- and postoperative AChE activity (U/gHb) and the development of POD (Odds ratio (OR), [95% confidence interval (CI)], preoperative 0.95 [0.89–1.00], postoperative 0.94 [0.89–1.00]). Conclusions We found an association between POD and AChE activity and provided new information considering patients with abdominal surgery. Future analyses should examine course dynamics of postoperative cholinesterase activities in order to clarify interactions between the cholinergic system and pathophysiological mechanisms leading to POD. Trial registration ClinicalTrials.gov: NCT02265263.

Abstract Objective Activated astroglia is involved in the pathophysiology of neurodegenerative diseases and has also been described in animal models of spinal muscular atrophy (SMA). Given the urgent need of biomarkers for treatment monitoring of new RNA‐modifying and gene replacement therapies in SMA, we examined glial fibrillary acidic protein concentrations in cerebrospinal fluid (cGFAP) as a marker of astrogliosis in SMA. Methods 58 adult patients and 21 children with genetically confirmed 5q‐associated SMA from four German motor neuron disease specialist care centers and 30 age‐ and sex‐matched controls were prospectively included in this study. cGFAP was measured and correlated to motor performance and disease severity. Additionally, we compared cGFAP with neurofilament light chain concentrations in cerebrospinal fluid (cNfL). Results cGFAP concentrations did not differ from controls but showed higher levels in more severely affected patients after adjustment for patients' age. Normalized cNfL values were associated with disease severity. Within 14 months of nusinersen treatment, cGFAP concentrations did not change, while cNfL decreased significantly. Interpretation cGFAP is not an outstanding biomarker in SMA, but might support the hypothesis that glial activation is involved in SMA pathology. Unlike previously suggested, cNfL may be a promising biomarker also in adult patients with SMA, which should be subject to further investigations.

Abstract Background The role of allogeneic hematopoietic cell transplantation (alloHCT) in acute myeloid leukemia (AML) with mutated IDH1/2 has not been defined. Therefore, we analyzed a large cohort of 3234 AML patients in first complete remission (CR1) undergoing alloHCT or conventional chemo-consolidation and investigated outcome in respect to IDH1/2 mutational subgroups (IDH1 R132C, R132H and IDH2 R140Q, R172K). Methods Genomic DNA was extracted from bone marrow or peripheral blood samples at diagnosis and analyzed for IDH mutations with denaturing high-performance liquid chromatography, Sanger sequencing and targeted myeloid panel next-generation sequencing, respectively. Statistical as-treated analyses were performed using R and standard statistical methods (Kruskal–Wallis test for continuous variables, Chi-square test for categorical variables, Cox regression for univariate and multivariable models), incorporating alloHCT as a time-dependent covariate. Results Among 3234 patients achieving CR1, 7.8% harbored IDH1 mutations (36% R132C and 47% R132H) and 10.9% carried IDH2 mutations (77% R140Q and 19% R172K). 852 patients underwent alloHCT in CR1. Within the alloHCT group, 6.2% had an IDH1 mutation (43.4% R132C and 41.4% R132H) and 10% were characterized by an IDH2 mutation (71.8% R140Q and 24.7% R172K). Variants IDH1 R132C and IDH2 R172K showed a significant benefit from alloHCT for OS (p = .017 and p = .049) and RFS (HR = 0.42, p = .048 and p = .009) compared with chemotherapy only. AlloHCT in IDH2 R140Q mutated AML resulted in longer RFS (HR = 0.4, p = .002). Conclusion In this large as-treated analysis, we showed that alloHCT is able to overcome the negative prognostic impact of certain IDH mutational subclasses in first-line consolidation treatment and could pending prognostic validation, provide prognostic value for AML risk stratification and therapeutic decision making.

Abstract Bile salt export pump (Bsep) (Abcb11)−/− mice are protected from acquired cholestatic injury due to metabolic preconditioning with a hydrophilic bile acid (BA) pool with formation of tetrahydroxylated bile acids (THBAs). We aimed to explore whether loss of Bsep and subsequent elevation of THBA levels may have immunomodulatory effects, thus improving liver injury in the multidrug resistance protein 2 (Mdr2) (Abcb4)−/− mouse. Cholestatic liver injury in Mdr2−/−Bsep−/− double knockout (DKO), Mdr2−/−, Bsep−/−, and wild‐type mice was studied for comparison. Mdr2−/− mice were treated with a THBA (3α,6α,7α,12α‐Tetrahydroxycholanoic acid). RNA/protein expression of inflammatory/fibrotic markers were investigated. Serum BA‐profiling was assessed by ultra‐performance liquid chromatography tandem mass spectrometry. Hepatic immune cell profile was quantified by flow cytometric analysis (FACS). In vitro, the THBA effect on chenodeoxycholic acid (CDCA)–induced inflammatory signaling in hepatocyte and cholangiocytes as well as lipopolysaccharide (LPS)/interferon‐γ (IFN‐γ)–induced macrophage activation was analyzed. In contrast to Mdr2−/−, DKO mice showed no features of sclerosing cholangitis. Sixty‐seven percent of serum BAs in DKO mice were polyhydroxylated (mostly THBAs), whereas Mdr2−/− mice did not have these BAs. Compared with Mdr2−/−, DKO animals were protected from hepatic inflammation/fibrosis. THBA feeding in Mdr2−/− mice improved liver injury. FACS analysis in DKO and Mdr2−/− THBA‐fed mice showed changes of the hepatic immune cell profile towards an anti‐inflammatory pattern. Early growth response 1 (EGR1) protein expression was reduced in DKO and in Mdr2−/− THBA‐fed mice compared with Mdr2−/− control mice. In vitro, THBA‐reduced CDCA induced EGR1 protein and mRNA expression of inflammatory markers in hepatocytes and cholangiocytes. LPS/IFN‐γ–induced macrophage activation was ameliorated by THBA. THBAs repress EGR1‐related key pro‐inflammatory pathways. Conclusion: THBA and their downstream targets may represent a potential treatment strategy for cholestatic liver diseases.

BackgroundInteractions between the somatosensory and motor cortices are of fundamental importance for motor control. Although physically distant, face and hand representations are side by side in the sensorimotor cortex and interact functionally. Traumatic brachial plexus injury (TBPI) interferes with upper limb sensorimotor function, causes bilateral cortical reorganization, and is associated with chronic pain. Thus, TBPI may affect sensorimotor interactions between face and hand representations.ObjectiveThe aim of this study was to investigate changes in hand–hand and face–hand sensorimotor integration in TBPI patients using an afferent inhibition (AI) paradigm.MethodThe experimental design consisted of electrical stimulation (ES) applied to the hand or face followed by transcranial magnetic stimulation (TMS) to the primary motor cortex to activate a hand muscle representation. In the AI paradigm, the motor evoked potential (MEP) in a target muscle is significantly reduced when preceded by an ES at short-latency (SAI) or long-latency (LAI) interstimulus intervals. We tested 18 healthy adults (control group, CG), evaluated on the dominant upper limb, and nine TBPI patients, evaluated on the injured or the uninjured limb. A detailed clinical evaluation complemented the physiological investigation.ResultsAlthough hand–hand SAI was present in both the CG and the TBPI groups, hand–hand LAI was present in the CG only. Moreover, less AI was observed in TBPI patients than the CG both for face–hand SAI and LAI.ConclusionOur results indicate that sensorimotor integration involving both hand and face sensorimotor representations is affected by TBPI.

Myotonic dystrophy type 1 (DM1), the most common form of adult-onset muscular dystrophy, is caused by a CTG expansion resulting in significant transcriptomic dysregulation that leads to muscle weakness and wasting. While strength training is clinically beneficial in DM1, molecular effects had not been studied. To determine whether training rescued transcriptomic defects, RNA-Seq was performed on vastus lateralis samples from 9 male patients with DM1 before and after a 12-week strength-training program and 6 male controls who did not undergo training. Differential gene expression and alternative splicing analysis were correlated with the one-repetition maximum strength evaluation method (leg extension, leg press, hip abduction, and squat). While training program–induced improvements in splicing were similar among most individuals, rescued splicing events varied considerably between individuals. Gene expression improvements were highly varied between individuals, and the percentage of differentially expressed genes rescued after training were strongly correlated with strength improvements. Evaluating transcriptome changes individually revealed responses to the training not evident from grouped analysis, likely due to disease heterogeneity and individual exercise response differences. Our analyses indicate that transcriptomic changes are associated with clinical outcomes in patients with DM1 undergoing training and that these changes are often specific to the individual and should be analyzed accordingly.

It is quite common for portal vein thrombosis to occur in subjects who present predisposing conditions such as cirrhosis, hepatobiliary malignancies, infectious or inflammatory abdominal diseases, or hematologic disorders. The incidence of idiopathic portal vein thrombosis in non-cirrhotic patients remains low, and despite the intensive workup that is performed in these cases, in up to 25% of cases, there is no identifiable cause. If portal vein thrombosis is untreated, complications arise and include portal hypertension, cavernous transformation of the portal vein, gastroesophageal and even small intestinal varices, septic thrombosis, or intestinal ischemia. However, intestinal ischemia develops as a consequence of arterial thrombosis or embolism, and the thrombosis of the mesenteric vein accounts for about 10% of cases of intestinal ischemia. Although acute superior mesenteric vein thrombosis can cause acute intestinal ischemia, its chronic form is less likely to cause acute intestinal ischemia, considering the possibility of developing collateral drainage. Ileus due to mesenteric venous thrombosis is rare, and only a small number of cases have been reported to date. Most patients experience a distinct episode of acute abdominal pain due to ischemia, and in the second phase, they develop an obstruction/ileus. Acute superior mesenteric venous thrombosis is a rare condition that is still associated with a high mortality rate. The management of such cases of superior mesenteric venous thrombosis is clinically challenging due to their insidious onset and rapid development. A prompt and accurate diagnosis followed by a timely surgical treatment is important to save patient lives, improve the patient survival rate, and conserve as much of the patient’s bowel as possible, thus leading to fewer sequelae.

The intricate mechanisms governing brain health and function have long been subjects of extensive investigation. Recent research has shed light on two pivotal systems, the glymphatic system and the endocannabinoid system, and their profound role within the central nervous system. The glymphatic system is a recently discovered waste clearance system within the brain that facilitates the efficient removal of toxic waste products and metabolites from the central nervous system. It relies on the unique properties of the brain’s extracellular space and is primarily driven by cerebrospinal fluid and glial cells. Conversely, the endocannabinoid system, a multifaceted signaling network, is intricately involved in diverse physiological processes and has been associated with modulating synaptic plasticity, nociception, affective states, appetite regulation, and immune responses. This scientific review delves into the intricate interconnections between these two systems, exploring their combined influence on brain health and disease. By elucidating the synergistic effects of glymphatic function and endocannabinoid signaling, this review aims to deepen our understanding of their implications for neurological disorders, immune responses, and cognitive well-being.

Objetives: This study investigated the levels of emotional intelligence in undergraduate psychology students, both males and females of a public university in Lambayeque as well as the levels of emotional intelligence according to sex, age and academic semester. Methodology: It is a descriptive study, which type of sampling was non probabilistic, snow ball type sampling for which participated 112 undergraduate students. The instrument used was the Baron Ice Emotional Intelligence Inventory of 133 items, 5-point Likert-scale. The findings show that 27.7% of the students report an average level of emotional intelligence and 10.7/% report a high level. Results: Regarding the levels according to sex, men presented a higher level of emotional intelligence (43%) in comparison to women (22%). Nevertheless, both sexes present an average level (30% and 26.8% respectively). With respect to age, results suggest that older students present an average level of emotional intelligence, according to 50% of the participants, for ages 27 and 31. Likewise, 32.40% of advanced semester students report an average level of emotional intelligence. Conclusions: Finally, it is concluded that the curricular training of psychology students must implement activities toward the development of emotional intelligence for future professional performance, considering the socio-cultural variables.

Abstract In a context of therapeutic revolution in older adults with AML, it is becoming increasingly important to select patients for the various treatment options by taking account of short-term efficacy and toxicity as well as long-term survival. Here, the data from three European registries for 1,199 AML patients aged 70 years or older treated with intensive chemotherapy were used to develop a prognostic scoring system. The median follow-up was 50.8 months. In the training set of 636 patients, age, performance status, secondary AML, leukocytosis, and cytogenetics, as well as NPM1 mutations (without FLT3-ITD), were all significantly associated with overall survival, albeit not to the same degree. These factors were used to develop a score that predicts long-term overall survival. Three risk-groups were identified: a lower, intermediate and higher-risk score with predicted 5-year overall survival (OS) probabilities of ≥12% (n = 283, 51%; median OS = 18 months), 3–12% (n = 226, 41%; median OS = 9 months) and

Aim of the study: To evaluate the association between temperature-humidity index (THI) and body condition score (BCS) at calving and retained placenta (RP), puerperal metritis, clinical ketosis, and mastitis in Holstein cows in a hot environment Area of study: Northeastern Mexico. Material and methods: This is a retrospective cohort study (n= 12,102 lactations from January 2017 to December 2021) using univariate logistic regressions. The outcome variables were periparturient diseases, and the predictor variables were BCS and thermal stress at calving. Main results: Cows calving with a THI > 82 were 30% more likely (prevalence 16.8% vs 13.7%; p < 0.01) to have RP than cows whose parturition occurred with moderate or low thermal stress (THI < 82 units). Cows calving with THI > 82 had significantly increased chances of having metritis than cows calving with THI < 82 (prevalence 15.6 vs 13.4; p < 0.01). Cows calving with a THI > 82 were 1.8 times more likely to have clinical ketosis (7.6% vs 4.4%; p < 0.01) than cows calving with THI < 82 units. Cows with BCS at calving ≥ 3.5 had half the risk of having RP (prevalence 10.4 vs 19.1%, p < 0.01) than cows with BCS < 3.5. Likewise, the risk of metritis decreased (p < 0.01) with BCS ≥3.5 at calving (prevalence 10.9 vs 17.4%). Research highlights: Heat stress at calving was associated with an increased risk for RP, puerperal metritis, and clinical ketosis compared to cows undergoing mild or no heat stress at parturition. Also, cows with BCS ≥ 3.5 were less likely to present RP and metritis, but high body fatness was associated with an increased risk for clinical ketosis.

Herein, we have displayed an easy way to produce monodisperse spinel nanoparticles (NPs) and the antifungal activity of CoFe2O4, Co0.5Zn0.5Fe2O4 and ZnFe2O4 nanostructures. Firstly, the structural, morphological and magnetic properties of each NP were investigated through x-ray diffraction (XRD), Transmission Electron Microscopy (TEM) and Vibrating Sample Magnetometer (VSM). The XRD data showed diffraction peaks related to the crystalline spinel phase. The TEM micrographs displayed monodisperse NPs with spherical morphology. The average sizes of CoFe2O4, Co0.5Zn0.5Fe2O4 and ZnFe2O4 NPs were 6.87 ± 0.05 nm, 5.18 ± 0.01 nm and 11.52 ± 0.09 nm, respectively. The VSM data indicated that the nanostructures are superparamagnetic at room temperature. Afterward, the antifungal properties of the Co/Zn-based ferrite NPs against Botrytis cinerea were tested. So, the inhibition of mycelial growth by different concentrations (45 – 360 ppm) of NPs was measured. The most effective nanostructure was CoFe2O4, with an EC50 value of 265 ppm. Further, to elucidate how the NPs are affecting B. cinerea, reactive oxygen species (ROS) production was measured. The results indicated that the CoFe2O4 monodisperse NPs could induce a burst of ROS in B. cinerea, promoting cellular damage.

Abstract Background Patients using immunosuppressive drugs may have unfavorable results after infections. However, there is a lack of information regarding COVID-19 in these patients, especially in patients with rheumatoid arthritis (RA). Therefore, the aim of this study was to evaluate the risk factors associated with COVID-19 hospitalizations in patients with RA. Methods This multicenter, prospective cohort study is within the ReumaCoV Brazil registry and included 489 patients with RA. In this context, 269 patients who tested positive for COVID-19 were compared to 220 patients who tested negative for COVID-19 (control group). All patient data were collected from the Research Electronic Data Capture database. Results The participants were predominantly female (90.6%) with a mean age of 53 ± 12 years. Of the patients with COVID-19, 54 (20.1%) required hospitalization. After multiple adjustments, the final regression model showed that heart disease (OR = 4.61, 95% CI 1.06–20.02. P

Abstract Background Extramedullary manifestations (EM) are rare in acute myeloid leukemia (AML) and their impact on clinical outcomes is controversially discussed. Methods We retrospectively analyzed a large multi-center cohort of 1583 newly diagnosed AML patients, of whom 225 (14.21%) had EM. Results AML patients with EM presented with significantly higher counts of white blood cells (p

Abstract Background B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a genetically heterogenous malignancy with poor prognosis in relapsed adult patients. The genetic basis for relapse in aneuploid subtypes such as near haploid (NH) and high hyperdiploid (HeH) BCP-ALL is only poorly understood. Pathogenic genetic alterations remain to be identified. To this end, we investigated the dynamics of genetic alterations in a matched initial diagnosis-relapse (ID-REL) BCP-ALL cohort. Here, we firstly report the identification of the novel genetic alteration CYB5Aalt, an alternative transcript of CYB5A, in two independent cohorts. Methods We identified CYB5alt in the RNAseq-analysis of a matched ID-REL BCP-ALL cohort with 50 patients and quantified its expression in various molecular BCP-ALL subtypes. Findings were validated in an independent cohort of 140 first diagnosis samples from adult BCP-ALL patients. Derived from patient material, the alternative open reading frame of CYB5Aalt was cloned (pCYB5Aalt) and pCYB5Aalt or the empty vector were stably overexpressed in NALM-6 cells. RNA sequencing was performed of pCYB5Aalt clones and empty vector controls followed by differential expression analysis, gene set enrichment analysis and complementing cell death and viability assays to determine functional implications of CYB5Aalt. Results RNAseq data analysis revealed non-canonical exon usage of CYB5Aalt starting from a previously undescribed transcription start site. CYB5Aalt expression was increased in relapsed BCP-ALL and its occurrence was specific towards the shared gene expression cluster of NH and HeH BCP-ALL in independent cohorts. Overexpression of pCYB5Aalt in NALM-6 cells induced a distinct transcriptional program compared to empty vector controls with downregulation of pathways related to reported functions of CYB5A wildtype. Interestingly, CYB5A wildtype expression was decreased in CYB5Aalt samples in silico and in vitro. Additionally, pCYB5Aalt NALM-6 elicited a more resistant drug response. Conclusions Across all age groups, CYB5Aalt was the most frequent secondary genetic event in relapsed NH and HeH BCP-ALL. In addition to its high subgroup specificity, CYB5Aalt is a novel candidate to be potentially implicated in therapy resistance in NH and HeH BCP-ALL. This is underlined by overexpressing CYB5Aalt providing first evidence for a functional role in BCL2-mediated apoptosis.

Abstract Background The impact of physiotherapy on insulin sensitivity and peripheral glucose metabolism in critically ill patients is not well understood. Methods This pooled analysis investigates the impact of different physiotherapeutic strategies on insulin sensitivity in critically ill patients. We pooled data from two previous trials in adult patients with sequential organ failure assessment score (SOFA)≥ 9 within 72 h of intensive care unit (ICU) admission, who received hyperinsulinaemic euglycaemic (HE) clamps. Patients were divided into three groups: standard physiotherapy (sPT, n = 22), protocol‐based physiotherapy (pPT, n = 8), and pPT with added muscle activating measures (pPT+, n = 20). Insulin sensitivity index (ISI) was determined by HE clamp. Muscle metabolites lactate, pyruvate, and glycerol were measured in the M. vastus lateralis via microdialysis during the HE clamp. Histochemical visualization of glucose transporter‐4 (GLUT4) translocation was performed in surgically extracted muscle biopsies. All data are reported as median (25th/75th percentile) (trial registry: ISRCTN77569430 and ISRCTN19392591/ethics approval: Charité‐EA2/061/06 and Charité‐EA2/041/10). Results Fifty critically ill patients (admission SOFA 13) showed markedly decreased ISIs on Day 17 (interquartile range) 0.029 (0.022/0.048) (mg/min/kg)/(mU/L) compared with healthy controls 0.103 (0.087/0.111), P

Abstract Objective Fatigue is a common and burdensome symptom of spinal muscular atrophy. Given its complex interactions, different dimensions of fatigue need to be investigated. The Multidimensional Fatigue Inventory is a widely used instrument that captures five distinct dimensions. The aim of this study was to investigate the validity and reliability of the German Multidimensional Fatigue Inventory in spinal muscular atrophy and to evaluate the presence of clinically relevant fatigue. Methods One hundred and forty adult spinal muscular atrophy patients completed the Multidimensional Fatigue Inventory in a nationwide, multicenter, cross‐sectional study. Structural validity was explored using principal component analysis. Cronbach’s α was calculated to evaluate internal consistency. Convergent validity was assessed by correlation with a Visual Analog Scale for fatigue and the EuroQol‐Five Dimension‐Five Level Scale as a measure of quality of life. Results The original five‐component model of the questionnaire constituted an acceptable fit. Internal consistency and convergent validity of general, physical, mental fatigue, and reduced activity were good. We observed a floor effect for mental fatigue. While physical fatigue exceeded the cutoff for clinically relevant fatigue, all dimensions but reduced motivation correlated negatively with quality of life. Age, depression, and ≥4 copies of the survival motor neuron 2 gene were associated with higher general/physical fatigue; unemployed participants reported higher scores for reduced activity/motivation. Interpretation The Multidimensional Fatigue Inventory is a valid and reliable instrument to assess different dimensions of fatigue in spinal muscular atrophy. Fatigue is a relevant problem in spinal muscular atrophy and its assessment should be incorporated into standard care.

E-cigarette use has been reported to affect cell viability, induce DNA damage, and modulate an inflammatory response resulting in negative health consequences. Most studies focus on oral and lung disease associated with e-cigarette use. However, tissue damage can be found in the cardio-vascular system and even the bladder. While the levels of carcinogenic compounds found in e-cigarette aerosols are lower than those in conventional cigarette smoke, the toxicants generated by the heat of the vaping device may include probable human carcinogens. Furthermore, nicotine, although not a carcinogen, can be metabolized to nitrosamines. Nitrosamines are known carcinogens and have been shown to be present in the saliva of e-cig users, demonstrating the health risk of e-cigarette vaping. E-cig vape can induce DNA adducts, promoting oxidative stress and DNA damage and NF-kB-driven inflammation. Together, these processes increase the transcription of pro-inflammatory cytokines. This creates a microenvironment thought to play a key role in tumorigenesis, although it is too early to know the long-term effects of vaping. This review considers different aspects of e-cigarette-induced cellular changes, including the generation of reactive oxygen species, DNA damage, DNA repair, inflammation, and the possible tumorigenic effects.

Prenatal hypoxia is associated with placental oxidative stress, leading to impaired fetal growth and an increased risk of cardiovascular disease in the adult offspring; however, the mechanisms are unknown. Alterations in mitochondrial function may result in impaired cardiac function in offspring. In this study, we hypothesized that cardiac mitochondrial function is impaired in adult offspring exposed to intrauterine hypoxia, which can be prevented by placental treatment with a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ). Cardiac mitochondrial respiration was assessed in 4-month-old rat offspring exposed to prenatal hypoxia (11% O2) from gestational day (GD)15–21 receiving either saline or nMitoQ on GD 15. Prenatal hypoxia did not alter cardiac mitochondrial oxidative phosphorylation capacity in the male offspring. In females, the NADH + succinate pathway capacity decreased by prenatal hypoxia and tended to be increased by nMitoQ. Prenatal hypoxia also decreased the succinate pathway capacity in females. nMitoQ treatment increased respiratory coupling efficiency in prenatal hypoxia-exposed female offspring. In conclusion, prenatal hypoxia impaired cardiac mitochondrial function in adult female offspring only, which was improved with prenatal nMitoQ treatment. Therefore, treatment strategies targeting placental oxidative stress in prenatal hypoxia may reduce the risk of cardiovascular disease in adult offspring by improving cardiac mitochondrial function in a sex-specific manner.

The increase in life expectancy among individuals over 65 years of age has changed the age pyramid of the Brazilian population. Quality of life (QoL) is an important parameter to assess health status. The aim of the study was to describe the QoL of elderly people enrolled in an elderly care program, showing associations with the characteristics of the patient, disease, therapy, and social support, contributing to improve care for the elderly who receive this service. This was a descriptive, quantitative, cross-sectional, correlational study with 85 individuals aged 60 years or more, who were literate, independent in activities of daily living, without diagnosed cognitive/psychological impairment, and who had been going to the Nossa Senhora do Rosário Social Center for at least one month. To collect the independent variables, an instrument developed by the authors was used; in addition to the Morisk-Green test and Medication Regimen Complexity Index (MRCI). QoL was assessed by WHOQOL-brief. 89.4% were women; 38.8% were 60 to 70 years old; 77.6% had up to 3 comorbidities, the most frequent was hypertension (77.65%); 49.41% used polypharmacy, the MRCI ranged from 2.5 to 48.0 points for one to twelve medications/day; 57.65% acquired their medication through the SUS; 64.80% had medium/low adherence; 43.53% declared having a good perception of health. As for the WHOQOL-brief domains, the highest mean was obtained in the social domain (75.5), followed by the psychological (68.3), physical (67.1), and environmental (64.8) domains. The results of this study highlighted that the female gender, presence of diseases, therapeutic complexity, and perception of poor health are associated with lower quality of life indices in this population.

We retrospectively studied 97 acute myeloid leukemia patients with trisomy 19 (median age at diagnosis 57 years; range, 17- 83 years) treated between 2001 and 2019 within two multicenter study groups. Trisomy 19 occurred alone in ten (10.5%) patients, with additional abnormalities being present in non-complex karyotypes in eight (8%) patients and in complex karyotypes in 79 (82%) patients. Altogether, karyotypes characterized by trisomies only were present in 27 (28%) patients. Data on response and outcome of intensively treated patients were available for 92 cases. The median follow-up was 6.4 years (95% confidence interval [95% CI]: 2.9-9.0 years). The complete remission (CR) rate after induction therapy was 52% (48 patients); the early death rate was 10% (n=9). Notably, patients with trisomy 19 as the sole abnormality had a CR rate of 89%. Allogeneic hematopoietic stem cell transplantation (allo-HCT) was performed in 34 (35%) patients (CR, n=19; active disease, n=15). Five-year relapse-free and overall survival rates were 26% (95% CI: 16-43%) and 20% (95% CI: 13-31%), respectively. Overall survival rates were significantly higher in patients with trisomy 19 as the sole abnormality or within karyotypes characterized by trisomies only (P=0.05). An Andersen-Gill model including allo-HCT as a time-dependent covariable on overall survival revealed that trisomy 19 as the sole abnormality or within karyotypes characterized by trisomies only was a favorable factor (hazard ratio [HR]=0.47; P=0.021); higher age at diagnosis had an adverse impact (10 years difference; HR=1.29; P=0.002), whereas allo-HCT did not have a beneficial impact (odds ratio=1.45; P=0.21). In our cohort, patients with trisomy 19 as the sole abnormality or within karyotypes characterized by trisomies only had a high CR rate and better clinical outcome.