bluuebunny/crossref_metadata_2025_split huggingface dataset:
3-Methylmethcathinone Intoxication: Discrepancies Between Blood Concentrations and Clinical Outcomes—A Short Communication
Authors: Drevin Guillaume , Baudriller Antoine , Ferec Severine , Beloncle François , Briet Marie , Abbara Chadi 
Published: September 2023

Background:The absence of a correlation between the blood concentration of 3-methylmethcathinone (3-MMC) and clinical outcomes in intoxication cases has been attributed to stability issues. Indeed, a loss of more than 50%, 70%, and even 95% of 3-MMC in whole blood after 2 weeks of storage at 20°C, 4°C, and room temperature, respectively, has been reported in the past. Here, the authors report the case of a 43-year-old man who was hospitalized with generalized convulsive status epilepticus related to 3-MMC use with a plasma concentration of 9600 ng/mL (delay between sampling and analysis <72 hours). The stability of 3-MMC was evaluated in several biological specimens.Methods:Three quality control samples (human plasma, whole blood, and postmortem blood) spiked with 3-MMC were stored at −20°C and 4°C for 14 days. The initial analysis was performed on day 1 to establish the initial concentration of 3-MMC in each specimen type, and the samples were divided into 2 aliquots for storage under both conditions. Further analyses were performed on days 7 and 14 for each specimen, and the results were compared with those obtained on day 1.Results:3-MMC appeared relatively stable in whole and postmortem blood when stored at −20°C for 1 week, with losses of <3% in both matrices (0% and 2.5%, respectively). At +4°C, 3-MMC losses ranged from 25% to 53%.Conclusions:These results differ from others reported in the literature. Hence, it may be hypothesized that other elements should be considered to explain the discrepancy between the concentration and toxicity pointed out by the Toxicology community, especially the development of tolerance.
Simultaneous Quantification of Psychotropic Drugs in Human Plasma and Breast Milk and Its Application in Therapeutic Drug Monitoring and Peripartum Treatment Optimization
Authors: Le Marois Marguerite , Doudka Natalia , Tzavara Eleni , Delaunay Laurence , Quaranta Sylvie , Blin Olivier , Belzeaux Raoul , Guilhaumou Romain 
Published: September 2023

Background:
Therapeutic drug monitoring is recommended for several psychotropic drugs, particularly in sensitive situations such as the peripartum period. This study aimed to develop an ultra-high-performance liquid chromatography–tandem spectrometry method for the simultaneous quantification of 14 psychotropic drugs in human plasma and 4 in breast milk.

Methods:
The samples were precipitated with methanol containing the stable isotope-labeled analogs. Chromatographic separation was performed using a Phenomenex Luna Omega Polar C18 column. Detection was performed using a triple-quadrupole mass spectrometer equipped with an electrospray ionization interface. The method was fully validated in plasma according to the European Guidelines on Bioanalytical Method Validation and partially validated in breast milk by determining the intraday precision and accuracy, linearity, lower limit of quantification, and matrix effect.

Results:
The correlation coefficients of the calibration curves were greater than 0.99. Coefficients of variation ranged from 3.05% to 14.66% and 0.62%–14.90% for internal standard-normalized matrix effect, 1.4%–14.1% and 2.1%–10.4% for intraday precision, and 3.2%–13.9% and 4.1%–9.6% for interday precision, in plasma and milk, respectively. The relative error in accuracy did not exceed ±15% for any analyte. The method was successfully applied clinically to measure the concentrations of psychotropic drugs in 952 plasma samples, among which 43% of the concentrations were out of the therapeutic range, and 13 breast milk samples, with calculated relative infant doses ranging from 0.32% to 8.18%.

Conclusions:
To the best of the authors' knowledge, this is the first routine technique validated for the quantification of psychotropic drugs in both plasma and breast milk, allowing for treatment optimization and prevention of adherence issues, including those in breastfeeding patients.
Direct Immunofluorescence Findings and Factors Affecting Conjunctival Biopsy Positivity in Ocular Mucous Membrane Pemphigoid
Authors: Jain Neha , Jakati Saumya , Shanbhag Swapna S. , Basu Sayan 
Published: September 2023

Purpose:
The aim of this study was to describe the direct immunofluorescence (DIF) findings and factors affecting conjunctival biopsy positivity in patients clinically diagnosed with ocular mucous membrane pemphigoid (OMMP).

Methods:
This retrospective observational case series included patients with clinical OMMP who underwent conjunctival biopsy for DIF in at least 1 eye between 2018 and 2021 in an institutional setting. The primary outcome measures were association of age and chronic ocular complications with biopsy positivity.

Results:
Of 61 patients, DIF positivity was seen in 33 (54.1%) clinically suspected cases of OMMP. Of 39 patients who underwent bilateral biopsy, 23 (59%) were positive, of which 12 (52%) were positive in both eyes while 11 (48%) were positive in 1 eye. Of 22 patients who underwent unilateral biopsy, 10 (45%) were positive. Of the 100 biopsied eyes, 45 (45%) were DIF positive. Among the immunoreactants studied, linear deposition of C3 was seen in all 45 positive eyes (100%). Increasing age was significantly associated with higher likelihood of biopsy negativity (P = 0.032), whereas a greater Sotozono chronic ocular complication score, indicative of disease severity, was associated with low likelihood of biopsy positivity (P = 0.0042) and lower overall expression of immunoreactants on DIF (P = 0.0007).

Conclusions:
Older patients and patients with more severe ocular surface disease sequelae are likely to have negative DIF results. To optimize the chances of confirming the diagnosis of OMMP by DIF, both eyes should be biopsied early in the disease course. If 1 eye is being biopsied, the less affected eye must be chosen.
Leukemia circulation kinetics revealed through blood exchange method
Authors: Miller Alex B. , Langenbucher Adam , Rodriguez Felicia H. , Lin Lin , Bray Christina , Duquette Sarah , Zhang Ye , Goulet Dan , Lane Andrew A. , Weinstock David M. , Hemann Michael T. , Manalis Scott R. 
Published: September 2023

AbstractLeukemias and their bone marrow microenvironment are known to undergo dynamic changes over the course of disease. However, relatively little is known about the circulation kinetics of leukemia cells, nor the impact of specific factors on the clearance of circulating leukemia cells (CLCs) from the blood. To gain a basic understanding of leukemia cell dynamics over the course of disease progression and therapeutic response, we apply a blood exchange method to mouse models of acute leukemia. We find that CLCs circulate in the blood for 1-2 orders of magnitude longer than solid tumor circulating tumor cells. We further observe that: i) leukemia presence in the marrow can limit the clearance of CLCs in a model of acute lymphocytic leukemia (ALL), and ii) CLCs in a model of relapsed acute myeloid leukemia (AML) can clear faster than their untreated counterparts. Our approach can also directly quantify the impact of microenvironmental factors on CLC clearance properties. For example, data from two leukemia models suggest that E-selectin, a vascular adhesion molecule, alters CLC clearance. Our research highlights that clearance rates of CLCs can vary in response to tumor and treatment status and provides a strategy for identifying basic processes and factors that govern the kinetics of circulating cells.
ParSE-seq: A Calibrated Multiplexed Assay to Facilitate the Clinical Classification of Putative Splice-altering Variants
Authors: O’Neill Matthew J. , Yang Tao , Laudeman Julie , Calandranis Maria , Solus Joseph , Roden Dan M. , Glazer Andrew M. 
Published: September 2023

AbstractBackgroundInterpreting the clinical significance of putative splice-altering variants outside 2-base pair canonical splice sites remains difficult without functional studies.MethodsWe developed Parallel Splice Effect Sequencing (ParSE-seq), a multiplexed minigene-based assay, to test variant effects on RNA splicing quantified by high-throughput sequencing. We studied variants in SCN5A, an arrhythmia-associated gene which encodes the major cardiac voltage-gated sodium channel. We used the computational tool SpliceAI to prioritize exonic and intronic candidate splice variants, and ClinVar to select benign and pathogenic control variants. We generated a pool of 284 barcoded minigene plasmids, transfected them into Human Embryonic Kidney (HEK293) cells and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), sequenced the resulting pools of splicing products, and calibrated the assay to the American College of Medical Genetics and Genomics scheme. Variants were interpreted using the calibrated functional data, and experimental data were compared to SpliceAI predictions. We further studied some splice-altering missense variants by cDNA-based automated patch clamping (APC) in HEK cells and assessed splicing and sodium channel function in CRISPR-edited iPSC-CMs.ResultsParSE-seq revealed the splicing effect of 224SCN5Avariants in iPSC-CMs and 244 variants in HEK293 cells. The scores between the cell types were highly correlated (R2=0.84). In iPSCs, the assay had concordant scores for 21/22 benign/likely benign and 24/25 pathogenic/likely pathogenic control variants from ClinVar. 43/112 exonic variants and 35/70 intronic variants with determinate scores disrupted splicing. 11 of 42 variants of uncertain significance were reclassified, and 29 of 34 variants with conflicting interpretations were reclassified using the functional data. SpliceAI computational predictions correlated well with experimental data (AUC = 0.96). We identified 20 uniqueSCN5Amissense variants that disrupted splicing, and 2 clinically observed splice-altering missense variants of uncertain significance had normal function when tested with the cDNA-based APC assay. A splice-altering intronic variant detected by ParSE-seq, c.1891-5C>G, also disrupted splicing and sodium current when introduced into iPSC-CMs at the endogenous locus by CRISPR editing.ConclusionsParSE-seq is a calibrated, multiplexed, high-throughput assay to facilitate the classification of candidate splice-altering variants.
A Systematic Review on the Effects of Exercise on Gut Microbial Diversity, Taxonomic Composition, and Microbial Metabolites: Identifying Research Gaps and Future Directions
Authors: Cullen John M.A. , Shahzad Shahim , Dhillon Jaapna 
Published: September 2023

AbstractThe gut microbiome, hosting a diverse microbial community, plays a pivotal role in metabolism, immunity, and digestion. While the potential of exercise to influence this microbiome has been increasingly recognized, findings remain incongruous. This systematic review examined the effects of exercise on the gut microbiome of human and animal models. Databases (i.e., PubMed, Cochrane Library, Scopus, and Web of Science) were searched up to June 2022. Thirty-two exercise studies, i.e., 19 human studies, and 13 animal studies with a minimum of two groups that discussed microbiome outcomes, such as diversity, taxonomic composition, or microbial metabolites, over the intervention period, were included in the systematic review (PROSPERO registration numbers: CRD42023394223 and CRD42023394485). Results indicated that over 50% of studies found no significant exercise effect on human microbial diversity. When evident, exercise often augmented the Shannon index, reflecting enhanced microbial richness and evenness, irrespective of disease status. Changes in beta-diversity metrics were also documented with exercise but without clear directionality. A larger percentage of animal studies demonstrated shifts in diversity compared to human studies, but without any distinct patterns, mainly due to the varied effects of predominantly aerobic exercise on diversity metrics. In terms of taxonomic composition, in humans, exercise usually led to a decrease in the Firmicutes/Bacteroidetes ratio, and consistent increases withBacteroidesandRoseburiagenera. In animal models,Coprococcus, a SCFA producer, consistently rose with exercise. Generally, SCFA producers were found to increase with exercise in animal models. With regard to metabolites, SCFAs emerged as the most frequently measured metabolite. However, due to limited human and animal studies examining exercise effects on microbial-produced metabolites, including SCFAs, clear patterns did not emerge. The overall risk of bias was deemed neutral. In conclusion, this comprehensive systematic review underscores that exercise can potentially impact the gut microbiome with indications of changes in taxonomic composition. The significant variability in study designs and intervention protocols demands more standardized methodologies and robust statistical models. A nuanced understanding of the exercise-microbiome relationship could guide individualized exercise programs to optimize health.
A beneficial synonymous substitution in EF-Tu is contingent on genetic background
Authors: McGrath Kaitlyn M. , Russell Steven J. , Fer Evrim , Garmendia Eva , Hosgel Ali , Baltrus David A. , Kaçar Betül 
Published: September 2023

AbstractSynonymous mutations are changes to DNA sequence that occur within translated genes but which do not affect the protein sequence. Although often referred to as silent mutations, evidence suggests that synonymous mutations can affect gene expression, mRNA stability, and even translation efficiency. A collection of both experimental and bioinformatic data has shown that synonymous mutations can impact cell phenotype, yet less is known about the molecular mechanisms and potential of beneficial or adaptive effects of such changes within evolved populations. Here, we report a beneficial synonymous mutation acquired via experimental evolution in an essential gene variant encoding the translation Elongation Factor protein EF-Tu. We demonstrate that this particular synonymous mutation increases EF-Tu mRNA and protein levels, as well as the polysome abundance on global transcripts. Although presence of the synonymous mutation is clearly causative of such changes, we also demonstrate that fitness benefits are highly contingent on other potentiating mutations present within the genetic background in which the mutation arose. Our results underscore the importance of beneficial synonymous mutations, especially those that affect levels of proteins that are key for cellular processes.ImportanceThis study explores the degree to which synonymous mutations in essential genes can influence adaptation in bacteria. An experimental system whereby anEscherichia colistrain harboring an engineered translation protein Elongation Factor-Tu (EF-Tu) was subjected to laboratory evolution. We find that a synonymous mutation acquired on the gene encoding for EF-Tu is conditionally beneficial for bacterial fitness. Our findings provide insight into the importance of the genetic background when a synonymous substitution is favored by natural selection and how such changes have the potential to impact evolution when critical cellular processes are involved.
Short-latency preference for faces in the primate superior colliculus
Authors: Yu Gongchen , Katz Leor N. , Quaia Christian , Messinger Adam , Krauzlis Richard J. 
Published: September 2023

AbstractFace processing is fundamental to primates and has been extensively studied in higher-order visual cortex. Here we report that visual neurons in the midbrain superior colliculus (SC) display a preference for faces, that the preference emerges within 50ms of stimulus onset – well before “face patches” in visual cortex – and that this activity can distinguish faces from other visual objects with accuracies of ∼80%. This short-latency preference in SC depends on signals routed through early visual cortex, because inactivating the lateral geniculate nucleus, the key relay from retina to cortex, virtually eliminates visual responses in SC, including face-related activity. These results reveal an unexpected circuit in the primate visual system for rapidly detecting faces in the periphery, complementing the higher-order areas needed for recognizing individual faces.One-Sentence SummaryAn unexpected circuit through the primate midbrain reports the presence of a face in peripheral vision in 1/20thof a second.
Hippo-deficient cardiac fibroblasts differentiate into osteochondroprogenitors
Authors: Tsai Chang-Ru , Kim Jong , Li Xiao , Czarnewski Paulo , Li Rich , Meng Fansen , Zheng Mingjie , Zhao Xiaolei , Steimle Jeffrey , Grisanti Francisco , Wang Jun , Samee Md. Abul Hassan , Martin James 
Published: September 2023

AbstractCardiac fibrosis, a common pathophysiology associated with various heart diseases, occurs from the excess deposition of extracellular matrix (ECM)1. Cardiac fibroblasts (CFs) are the primary cells that produce, degrade, and remodel ECM during homeostasis and tissue repair2. Upon injury, CFs gain plasticity to differentiate into myofibroblasts3and adipocyte-like4,5and osteoblast-like6cells, promoting fibrosis and impairing heart function7. How CFs maintain their cell state during homeostasis and adapt plasticity upon injury are not well defined. Recent studies have shown that Hippo signalling in CFs regulates cardiac fibrosis and inflammation8–11. Here, we used single-nucleus RNA sequencing (snRNA-seq) and spatially resolved transcriptomic profiling (ST) to investigate how the cell state was altered in the absence of Hippo signaling and how Hippo-deficient CFs interact with macrophages during cardiac fibrosis. We found that Hippo-deficient CFs differentiate into osteochondroprogenitors (OCPs), suggesting that Hippo restricts CF plasticity. Furthermore, Hippo-deficient CFs colocalized with macrophages, suggesting their intercellular communications. Indeed, we identified several ligand-receptor pairs between the Hippo-deficient CFs and macrophages. Blocking the Hippo-deficient CF-induced CSF1 signaling abolished macrophage expansion. Interestingly, blocking macrophage expansion also reduced OCP differentiation of Hippo-deficient CFs, indicating that macrophages promote CF plasticity.
SNPred outperforms other ensemble-based SNV pathogenicity predictors and elucidates the challenges of using ClinVar for evaluation of variant classification quality
Authors: Molotkov Ivan , Koboldt Daniel C. , Artomov Mykyta 
Published: September 2023

AbstractBackgroundCurrent single nucleotide variants (SNVs) pathogenicity prediction tools assess various properties of genetic variants and provide a likelihood of causing a disease. This information aids in variant prioritization – the process of narrowing down the list of potential pathogenic variants, and, therefore, facilitating diagnostics. Assessing the effectiveness of SNV pathogenicity tools using ClinVar data is a widely adopted practice. Our findings demonstrate that this conventional method tends to overstate performance estimates.MethodsWe introduce SNPred, an ensemble model specifically designed for predicting the pathogenicity of nonsynonymous single nucleotide variants (nsSNVs). To evaluate its performance, we conducted assessments using six distinct validation datasets derived from ClinVar andBRCA1Saturation Genome Editing (SGE) data.ResultsAcross all validation scenarios, SNPred consistently outperformed other state-of-the-art tools, particularly in the case of rare and cancer-related variants, as well as variants that are classified with low confidence by mostin silicotools. To ensure convenience, we provide precalculated scores for all possible nsSNVs.We proved that the exceptionally high accuracy scores of the best models achieved for ClinVar variants are only attainable if the models learn to replicate misclassifications found in ClinVar. Additionally, we conducted a comparison of predictor performance on two distinct sets of BRCA1 variants that did not overlap: one sourced from ClinVar and the other from the SGE study. Across allin silicopredictors, we observed a significant trend where ClinVar variants were classified with notably higher accuracy.ConclusionsWe provide a powerful variant pathogenicity predictor that enhances the quality of clinical variant interpretation and highlights important challenges of using ClinVar for SNV pathogenicity predictors evaluation.
Early combination with remdesivir, nirmatrelvir/ritonavir and sotrovimab for the treatment of COVID-19 in immunocompromised hosts
Authors: Gentile Ivan , Foggia Maria , Silvitelli Maria , Sardanelli Alessia , Cattaneo Letizia , Viceconte Giulio ,   Federico II COVID team
Published: September 2023

AbstractBackgroundImmunocompromised patients with COVID-19 have higher morbidity and mortality than general population. Some authors have successfully used antiviral combination, but never in the early phase of the infection.MethodsRetrospective cohort study to describe efficacy and safety of the combination of 2 antivirals, with or without a mAb, both in early (within 10 days from symptoms) and in later phase (after 10 days) of SARS-CoV-2 infection in immunocompromised patients admitted to our facility.ResultsWe treated 11 patients (7 in early phase and 4 in later phase of COVID-19) with 10 days of intravenous remdesivir plus 5 days of oral nirmatelvir/ritonavir, also combined with sotrovimab in 10/11 cases.Notably, 100% of the “early” patients reached virological clearance at day 30 from the end of the therapy and were alive and well at follow-up, whereas corresponding figures in the “late” patients were 50% and 75%. Patients in late group more frequently needed oxygen supplementation (p=0.015) and steroid therapy (p=0.045) during admission and reached higher a COVID-19 severity (p=0.017).DiscussionThe combination of antiviral and sotrovimab in early phase of COVID-19 in immunocompromised patients is well tolerated and associated with 100% of virological clearance. Patients treated later have lower response rate and higher disease severity, but a causative role of the therapy in such finding is yet to be demonstrated.
Prevalence and Associated Factors of Chronic Illness among Adults in Somalia: Findings from the Somali Health and Demographic Survey 2018-2019
Authors: Jayte Mohamed 
Published: September 2023

AbstractBackgroundThe distribution and related determinants of chronic diseases remain poorly characterized in Somalia, despite an emerging burden. The 2018-2019 Somali Health and Demographic Survey (SHDS) offers an opportunity to address evidence gaps regarding chronic conditions in Somalia.ObjectivesThis study aimed to determine the prevalence of chronic illnesses and analyze related sociodemographic factors among adults aged ≥18 years in Somalia using data from the SHDS.MethodsThe analysis was conducted using cross-sectional SHDS data gathered from 31,198 households. Prevalence of self-reported chronic diseases was evaluated for the adult sample (n=23,485). Multivariable logistic regression examined sociodemographic factors associated with having a chronic condition.ResultsApproximately one in twelve adults (8.3%, 95% CI 7.9-8.6) had at least one chronic condition, with greater prevalence among women, urban dwellers, older individuals, and those having secondary education or higher. The most prevalent conditions were hypertension (26%), arthritis (15%), diabetes (11%), and asthma (8%). Advanced age, female gender, urban residence, and elevated wealth status were associated with higher likelihood of having a chronic disease.ConclusionsChronic diseases affect a substantial proportion of Somali adults, with heightened prevalence among growing urban populations. Integrative policies and programs are crucial for addressing the increasing burden of chronic conditions in conjunction with demographic changes