bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic Variability of Sulthiame: The Impact of Age, Drug–Drug Interactions, and Biochemical Markers of Toxicity in Patients with Epilepsy
Authors: Heger Katrine , Kjeldstadli Kari , Ring Nelly , Aaberg Kari Modalsli , Kjeldsen Signe Flood , Burns Margrete Larsen , Johannessen Svein I. , Johannessen Landmark Cecilie 
Published: December 2023

Purpose:
Sulthiame is an antiseizure medication increasingly used for epilepsy. The aim of this study was to investigate the pharmacokinetic variability of sulthiame in children and adults with epilepsy with respect to age, comedication, dose, serum concentration, and biochemical markers of toxicity in a clinical setting.

Method:
Retrospective quantitative data from the therapeutic drug monitoring (TDM) database at the Section for Clinical Pharmacology, the National Center for Epilepsy, Norway (2015–2021), were used.

Results:
TDM data from 326 patients (127 female/199 male) were included [mean age, 11.4 (range 2–44) years; mean weight, 41 (range 14–109) kg]. Interindividual pharmacokinetic variability in the concentration/(dose/body weight) (C/(D/kg)) ratio was 16-fold; intraindividual variability was up to 8-fold (coefficient of variation = 10%–78%). Young children (younger than 6 years) had a significantly lower C/(D/kg) ratio than older age groups (P < 0.05). Various comedications did not significantly affect the C/(D/kg) ratio, possibly owing to the small sample size. However, CYP2C19-mediated inhibition by sulthiame was indicated because patients using clobazam and sulthiame (n = 28) had a 3.5-fold higher N-desmethylclobazam C/(D/kg) ratio than those using neutral comedication (n = 45; P < 0.001). Patients with pH values below the adjusted normal range (7.32–7.42; n = 15) had a 33% higher sulthiame concentration than those with normal pH values (n = 22; P < 0.05). Blood gas measurements, especially pH, may serve as markers of toxicity and can be used in combination with clinical data when toxicity is suspected.

Conclusions:
This study revealed the extensive intraindividual and interindividual pharmacokinetic variability of sulthiame, with age as a contributing factor. Sulthiame has clinically relevant interactions with clobazam. The use of TDM and pH as a biochemical marker may contribute to individualized and safe sulthiame treatment.
Bronchoscopic Electrocautery Versus Adrenaline and Cold Saline Instillation for Prophylactic Haemostasis Prior to Biopsy of Endobronchial Lesions (BEVACS)
Authors: Shahul S Aneesa , Chauhan Nishant Kumar , Dutt Naveen , Chakraborti Amartya , Elhence Poonam , Jalandra Ramniwas 
Published: December 2023

Background:
Flexible bronchoscopy-guided endobronchial biopsy (EBB) is routinely performed as an outpatient daycare procedure. Bleeding after EBB is a common complication, that at times disrupts the procedure and can rarely lead to a catastrophe. We aimed to compare the efficacy of prebiopsy prophylactic bronchoscopic electrocautery with adrenaline and cold saline instillation in achieving hemostasis in patients with endobronchial lesions with a higher risk of bleeding during EBB.

Methods:
In this open-label, randomized controlled trial, 60 patients with endobronchial lesions were randomized to either the prophylactic electrocautery arm or the adrenaline and cold saline arm. Postbiopsy endobronchial bleed was quantified in millimeters using the Visual Analog Scale (VAS) and graded as per the British Thoracic Society grading system. Electrocautery-induced tissue damage was graded by the pathologist as “no damage,” “mild,” “moderate,” and “severe.”

Results:
The median VAS score of bleeding was 6.14 mm (interquartile range: 8 mm) in the electrocautery arm and 10.17 mm (interquartile range: 7 mm) in the adrenaline and cold saline arm. Though the difference in the VAS score of bleeding between the two groups was statistically significant, there was no significant difference in the proportion of grade 2 or higher bleeding.

Conclusion:
No difference in postbiopsy bleed was observed between the application of electrocautery or instillation of cold saline plus adrenaline before biopsy of those endobronchial lesions which were likely to bleed more after biopsy. Although controlled prophylactic electrocautery using 15 watts did not impair the quality of EBB specimens, a higher wattage may change this observation, as well as the bleeding quantity.
Effectiveness of Integrated Mindfulness-Based Fitness Training Program in Ameliorating Physical Symptoms and Survivor Concerns in Patients With Breast Cancer
Authors: Chang Yun-Chen 
Published: December 2023

BackgroundPatients with breast cancer typically experience both mental and physical distress after aggressive treatments. Some studies have explored the use of integrated interventions, such as mindfulness-based or exercise-based approaches, to reduce these symptoms. However, the results of these studies have been conflicting.ObjectiveThe aim of this study was to evaluate the effectiveness of an integrated mindfulness-based fitness training (MBFT) program in addressing overactive bladder, fear of cancer recurrence, and female sexual function in patients with breast cancer.MethodsFifty patients with breast cancer were either assigned to an 8-week MBFT group or a waitlist control group. The postintervention and preintervention scores were compared using descriptive analysis of the data set, as well as paired and independentttests.ResultsThere was no significant improvement in overactive bladder symptoms. Significant differences were observed in survivor concerns for items related to future diagnostic tests (t= 2.667,P= .024; 95% confidence interval [CI], 0.120–1.335), another type of cancer (t= 2.667,P= .024; 95% CI, 0.120–1.335), cancer coming back (t= 4.183,P= .002; 95% CI, 0.297–0.975), dying (t= 2.609,P= .026; 95% CI, 0.093–1.180), and my health (t= 2.887,P= .016; 95% CI, 0.104–0.805). A significant difference was found in the item measuring overall sexual life satisfaction (t= −3.162,P= .013) and sexual desire (MBFT vs waitlist control group, 2.00 vs 1.18;P= .023).ConclusionMindfulness-based fitness training interventions were effective in enhancing the well-being of patients with breast cancer by reducing fear of recurrence and enhancing sexual function. These findings support the use of MBFT as complementary therapy.Implications for PracticeHealthcare providers should carefully assess the individual needs and preferences of each patient and tailor interventions accordingly. In addition, integrating multiple approaches may be more effective in reducing distress.
Causal association of the brain structure with the risk of knee osteoarthritis: A large-scale genetic correlation study
Authors: Ruan Zhe , Lin Shaohai , Liu Zhi , Chen Peng , Xie Tongtong , Meng Li , Long Haitao , Zhao Shushan 
Published: December 2023

AbstractObjectivesObservational studies have shown the association between knee osteoarthritis (KOA) and neurological disorders with alterations in brain imaging-derived phenotypes (BIDPs). This study aimed at investigating whether alterations in brain structure are correlated with the occurrence of KOA.MethodsBased on the summary data from two large scale genome-wide association studies (GWASs), we performed a bidirectional two-sample Mendelian randomization (MR) analysis using single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) to determine the potential causal relationships between KOA and BIDPs.ResultsWe identified the genetic correlations of 152 BIDPs with KOA using linkage disequilibrium score regression. MR analysis revealed that increased volume but decreased intensity-contrast of bilateral nucleus accumbens (NAc), as well as increased left paracentral area was positively causally associated with KOA risk. For the IDPs of structural connectivity, we identified causal associations between multiple increased DTI parameter indicators of corticospinal tract (CST) and KOA. Inversely, KOA was positively correlated with the thickness and intensity-contrast of the rostral anterior cingulate, as well as the intensity-contrast of caudal anterior cingulate, insula cortex, and the grey matter volume of pallidum.ConclusionOur study supported bidirectional causal associations between KOA and BIDPs, which may provide new insights into the interaction of KOA with structural alterations in the nervous system.
Hybrid immunity from SARS-CoV-2 infection and vaccination in Canadian adults: cohort study
Authors: Brown Patrick E. , Fu Sze Hang , Newcombe Leslie , Tang Xuyang , Nagelkerke Nico , Birnboim H Chaim , Bansal Aiyush , Colwill Karen , Mailhot Geneviève , Delgado-Brand Melanie , Tursun Tulunay , Qi Freda , Gingras Anne-Claude , Slutsky Arthur S. , Pasic Maria D. , Companion Jeffrey , Bogoch Isaac I. , Morawski Ed , Lam Teresa , Reid Angus , Jha Prabhat ,   Ab-C Study Collaborators
Published: December 2023

AbstractBackgroundFew national-level studies have evaluated the impact of “hybrid” immunity (vaccination coupled with recovery from infection) from the Omicron variants of SARS-CoV-2.MethodsFrom May 2020 to December 2022, we conducted serial assessments (each of ∼4000-9000 adults) examining SARS-CoV-2 antibodies within a mostly representative Canadian cohort drawn from a national online polling platform. Adults, most of whom were vaccinated, reported viral test–confirmed infections and mailed self-collected dried blood spots to a central lab. Samples underwent highly sensitive and specific antibody assays to spike and nucleocapsid protein antigens, the latter triggered only by infection. We estimated cumulative SARS-CoV-2 incidence prior to the Omicron period and during the BA.1/1.1 and BA.2/5 waves. We assessed changes in antibody levels and in age-specific active immunity levels.ResultsSpike levels were higher in infected than in uninfected adults, regardless of vaccination doses. Among adults vaccinated at least thrice and infected more than six months earlier, spike levels fell notably and continuously for the nine months post-vaccination. By contrast, among adults infected within six months, spike levels declined gradually. Declines were similar by sex, age group, and ethnicity. Recent vaccination attenuated declines in spike levels from older infections. In a convenience sample, spike antibody and cellular responses were correlated. Near the end of 2022, about 35% of adults above age 60 had their last vaccine dose more than six months ago, and about 25% remained uninfected. The cumulative incidence of SARS-CoV-2 infection rose from 13% (95% CI 11-14%) before omicron to 78% (76-80%) by December 2022, equating to 25 million infected adults cumulatively. However, the COVID-19 weekly death rate during the BA.2/5 waves was less than half of that during the BA.1/1.1 wave, implying a protective role for hybrid immunity.ConclusionsStrategies to maintain population-level hybrid immunity require up-to-date vaccination coverage, including among those recovering from infection. Population-based, self-collected dried blood spots are a practicable biological surveillance platform.FundingFunding was provided by the COVID-19 Immunity Task Force, Canadian Institutes of Health Research, Pfizer Global Medical Grants, and St. Michael’s Hospital Foundation. PJ and ACG are funded by the Canada Research Chairs Program.
Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy
Authors: Wang Hui , Chang Timothy S , Dombroski Beth A , Cheng Po-Liang , Patil Vishakha , Valiente-Banuet Leopoldo , Farrell Kurt , Mclean Catriona , Molina-Porcel Laura , Rajput Alex , De Deyn Peter Paul , Bastard Nathalie Le , Gearing Marla , Kaat Laura Donker , Van Swieten John C , Dopper Elise , Ghetti Bernardino F , Newell Kathy L , Troakes Claire , de Yébenes Justo G , Rábano-Gutierrez Alberto , Meller Tina , Oertel Wolfgang H , Respondek Gesine , Stamelou Maria , Arzberger Thomas , Roeber Sigrun , Müller Ulrich , Hopfner Franziska , Pastor Pau , Brice Alexis , Durr Alexandra , Ber Isabelle Le , Beach Thomas G , Serrano Geidy E , Hazrati Lili-Naz , Litvan Irene , Rademakers Rosa , Ross Owen A , Galasko Douglas , Boxer Adam L , Miller Bruce L , Seeley Willian W , Van Deerlin Vivanna M , Lee Edward B , White Charles L , Morris Huw , de Silva Rohan , Crary John F , Goate Alison M , Friedman Jeffrey S , Leung Yuk Yee , Coppola Giovanni , Naj Adam C , Wang Li-San ,   PSP genetics study group, Dickson Dennis W , Höglinger Günter U , Schellenberg Gerard D , Geschwind Daniel H , Lee Wan-Ping 
Published: December 2023

AbstractBackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs).MethodIn this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed.ResultsOur analysis of common SNVs and indels confirmed known genetic loci atMAPT,MOBP, STX6,SLCO1A2,DUSP10, andSP1, and further uncovered novel signals inAPOE,FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer’s disease (AD), we observed theAPOEε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association inZNF592and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, includingIGH,PCMT1,CYP2A13, andSMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P= 6.73×10-3) in PSP.ConclusionsThrough WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.
Stimulus-related modulation in the 1/f spectral slope suggests an impaired inhibition of irrelevant information in people with multiple sclerosis
Authors: Akbarian Fahimeh , Rossi Chiara , Costers Lars , D’hooghe Marie B , D’haeseleer Miguel , Nagels Guy , Van Schependom Jeroen 
Published: December 2023

AbstractBackgroundMultiple sclerosis (MS) is an inflammatory and neurodegenerative disease characterized by neuronal and synaptic loss, resulting in an imbalance of excitatory and inhibitory synaptic transmission. MS leads to cognitive impairment such as reduced information processing speed and impaired working memory (WM). Recent studies have suggested that the 1/f slope of EEG/MEG power spectra can be associated with the excitation/inhibition (E/I) balance. A normal E/I balance is crucial for normal information processing and working memory.MethodsWe analyzed magnetoencephalographic (MEG) recordings of 38 healthy control subjects and 79 people with multiple sclerosis (pwMS) while performing an n-back working task. We computed and compared the steepness of the 1/f spectral slope through the FOOOF algorithm in the time windows [-1 0] and [0 1] s peristimulus time for both target and distractor stimulus for each brain parcel and for different working memory loads (0-back, 1-back, 2-back).ResultsThe spectral slope was significantly steeper after the stimulus onset and was correlated with reaction time. We also observed a steeper 1/f slope after distractor stimuli in healthy subjects compared to pwMS. Finally, we observed significant correlations between the 1/f spectral slope modulation and visuospatial working memory functioning in both healthy subjects and pwMS.ConclusionOur findings are consistent with an increased inhibition following stimulus onset. In pwMS, this increase is reduced, suggesting dysfunctional inhibition of irrelevant information. Finally, this impaired modulation is significantly associated with a pencil-paper test of visuospatial working memory.HighlightsThe flatter 1/f slope after distractor stimuli in people with multiple sclerosis (pwMS) compared to healthy subjects suggests a less pronounced inhibition of irrelevant information in pwMS.The significantly flatter 1/f slope was observed in the left inferior dorsal prefrontal cortex of pwMS in both 1-back and 2-back conditions. This particular brain parcel is known for its key role in motor planning, and the maintenance of sustained attention and working memory and executive functions.A steeper 1/f slope after target and distractor stimuli suggests an increase in inhibition following stimulus onset in both healthy controls (HCs) and people with MS (pwMS).The 1/f slope modulation correlates with visuospatial working memory performance.
WITHDRAWN: Phylogenetic Analysis Detected Newly Identified Phylogroups in UropathogenicEscherichia coliIsolates in Iraq
Authors: Hamza Hiba J. , Al-Hasnawy Huda H. , Mohammad Layth Jasim , Judi Mohammed R. , Al-Shirifi Hider M.H. , Karimi Isaac , Yakhchalian Nima 
Published: December 2023

Withdrawal StatementmedRxiv has withdrawn this manuscript as it was submitted and made public without the full consent of all the authors. Therefore, this work should not be cited as reference for the project. If you have any questions, please contact the corresponding author.
Air cleaners and respiratory infections in schools: A modeling study using epidemiological, environmental, and molecular data
Authors: Banholzer Nicolas , Jent Philipp , Bittel Pascal , Zürcher Kathrin , Furrer Lavinia , Bertschinger Simon , Weingartner Ernest , Ramette Alban , Egger Matthias , Hascher Tina , Fenner Lukas 
Published: December 2023

AbstractBackgroundUsing a multiple-measurement approach, we examined the real-world effectiveness of portable HEPA-air filtration devices (air cleaners) in a school setting.MethodsWe collected environmental (CO2, particle concentrations), epidemiological (absences related to respiratory infections), audio (coughing), and molecular data (bioaerosol and saliva samples) over seven weeks during winter 2022/2023 in two Swiss secondary school classes. Using a cross-over study design, we compared particle concentrations, coughing, and the risk of infection with vs without air cleaners.ResultsAll 38 students (age 13−15 years) participated. With air cleaners, mean particle con-centration decreased by 77% (95% credible interval 63%−86%). There were no differences in CO2levels. Absences related to respiratory infections were 22 without vs 13 with air cleaners. Bayesian modeling suggested a reduced risk of infection, with a posterior probability of 91% and a relative risk of 0.73 (95% credible interval 0.44−1.18). Coughing also tended to be less frequent (posterior probability 93%). Molecular analysis detected mainly non-SARS-CoV-2 viruses in saliva (50/448 positive), but not in bioaerosols (2/105 positive) or HEPA-filters (4/160). The detection rate was similar with vs without air cleaners. Spatiotemporal analysis of positive saliva samples identified several likely transmissions.ConclusionsAir cleaners improved air quality, showed a potential benefit in reducing respiratory infections, and were associated with less coughing. Airborne detection of non-SARS-CoV-2 viruses was rare, suggesting that these viruses may be more difficult to detect in the air. Future studies should examine the importance of close contact and long-range transmission, and the cost-effectiveness of using air cleaners.
Sudden shifts in expression after small-scale duplication in vertebrates and strong support for the ortholog conjecture
Authors: Begum Tina , Duchen Pablo , Bucao Christabel Floi , Robinson-Rechavi Marc 
Published: December 2023

AbstractGene duplication is a potential source of innovation, but the evolutionary dynamics of functional change are still poorly understood. Under the debated “ortholog conjecture”, most functional change and innovation is assumed to follow duplication. Testing the ortholog conjecture allows to better understand and characterize the way in which gene function evolves. Most models of functional evolution assume continuous change, an assumption which we challenge here. We have applied a Lévy model of evolutionary trait jumps to the evolution of gene expression in vertebrates, with a special focus on duplication in teleost fishes. We show for the first time that trait jumps strongly affects paralogs, in addition to other modes of functional evolution. We find that at least 25% of teleost fish small-scale duplicates follow a rapid evolutionary rate shift model for both expression level and tissue-specificity, much more than after speciations. However, genome-wide duplicates (ohnologs) do not support such a trait jump model, and thus follow a different evolutionary dynamic. While there is some evidence for more positive selection at the protein-coding level after duplication, it is not strongly linked to jumps in expression. Finally, both small-scale paralogs and ohnologs strongly support the ortholog conjecture by contrasting speciation branches pre- and post-duplication to the duplication branches themselves, with trait jumps explaining much of the higher phylogenetic independent contrasts between small-scale paralogs.Significance statementThe debate on the ortholog conjecture, i.e. that gene function changes little between orthologs but changes frequently between paralogs, provides a framework to understand better the evolution of gene function. Here we add two pieces to the puzzle: a novel way to use phylogenetic contrasts to test the ortholog conjecture, by comparing not only duplication to speciation, but speciation according to whether they were preceded by a duplication; and a model of jumps rather than continuous change of gene function. We tested these on vertebrates, with emphasis on teleost fishes, distinguishing small-scale duplications and whole-genome duplication; in all cases we support strongly the ortholog conjecture. We find that trait jumps strongly affect small-scale paralogs but not genome duplication paralogs, providing an exciting new model for gene function evolution.