bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and Viral Dynamics of Tecovirimat in Patients with MPOX: A Multicenter Open-Label, Double-Arm Trial in Japan
Authors: Akiyama Yutaro , Morioka Shinichiro , Tsuzuki Shinya , Yoshikawa Tomoki , Yamato Masaya , Nakamura Hideta , Shimojima Masayuki , Takakusaki Mizue , Saito Sho , Takahashi Kozue , Sanada Mio , Komatsubara Mika , Takebuchi Kahoru , Yamaguchi Etsuko , Suzuki Tetsuya , Shimokawa Komei , Kurosu Takeshi , Kawahara Madoka , Oishi Kohei , Ebihara Hideki , Ohmagari Norio 
Published: August 2023

AbstractIntroductionTecovirimat’s application in treating mpox remains under-researched, leaving gaps in clinical and virological understanding.MethodsThe Tecopox study, conducted in Japan, assessed the efficacy and safety of oral tecovirimat therapy in patients with smallpox or mpox. Patients with mpox enrolled between June 28, 2022, and April 30, 2023, were included. We gathered demographic and clinical details along with blood, urine, pharyngeal swab, and skin lesion samples for viral analysis. A multivariable Tobit regression model was employed to identify factors influencing prolonged viral detection.ResultsNineteen patients were allocated to the tecovirimat group. The median age was 38.5 years, and all were male. Ten patients (52.6%) were infected with the human immunodeficiency virus (HIV). Sixteen patients (84.2%) had severe disease. Nine of the 15 patients (60.0%) (four patients withdrew before day 14) had negative PCR results for skin lesion specimens 14 days after inclusion. The mortality rates on days 14 and 30 were 0% and 0%, respectively. No severe adverse events were reported. HIV status and the number of days from symptom onset to tecovirimat administration were associated with lower Ct values (p= 0.027 and p < 0.001, respectively). The median number of days when PCR testing did not detect the mpox virus in each patient was 19.5 days.ConclusionThe results suggest that early tecovirimat administration might reduce viral shedding duration, thereby mitigating infection spread. Moreover, patients infected with HIV appeared to have prolonged viral shedding, increasing the transmission risk compared to those without HIV.KeypointsThe Tecopox study revealed that early tecovirimat administration might reduce viral shedding duration, thereby mitigating infection spread. Moreover, patients infected with HIV appeared to have prolonged viral shedding, increasing the transmission risk compared to those without HIV.
A Retrospective Cohort Study of the 2018 Angiotensin Receptor Blocker (ARB) Recalls and Subsequent Drug Shortages on Patients with Hypertension
Authors: Devine Joshua W , Tadrous Mina , Hernandez Inmaculada , Callaway Kim Katherine , Rothenberger Scott D , Mukhopadhyay Nandita , Gellad Walid F , Suda Katie J 
Published: August 2023

ABSTRACTPurposeIn July 2018, the Food and Drug Administration recalled valsartan due to carcinogenic impurities, leading to an unprecedented drug shortage leading to management challenges impacting a large population of valsartan users. However, the extent to which the valsartan recall impacted clinical outcomes is unknown. Our objective was to compare the risk of adverse events between patients with hypertension using valsartan and a propensity-score-matched group of patients using non-recalled angiotensin receptor blockers (ARBs) and angiotensin converting enzyme-inhibitors (ACE-Is).MethodsWe conducted a retrospective cohort analysis of Optum’s de-identified Clinformatics® Datamart (July 2017–January 2019). Adults with hypertension who received valsartan were compared to persons who received non-recalled ARBs and ACE-Is for 1 year prior to and on the recall date. The primary outcomes were measured in the 6 months following the recall date included: 1) a composite measure of all-cause hospitalization, all-cause emergency department (ED) and all-cause urgent care (UC) visit, 2) a composite cardiac event measure of hospitalizations for acute myocardial infarction and hospitalizations/ED/UC visits for stroke/transient ischemic attack, heart failure or hypertension. Cox proportional hazard models compared the risk of outcomes between propensity-score-matched treatment groups.ResultsOf adults with hypertension, 76,934 received valsartan at the time of the recall and 509,742 received a non-recalled ARB/ACE-I. Valsartan use at the time of the recall was associated with a combined increased risk of all-cause hospitalization, ED or UC use (HR 1.02; 95% CI: 1.00–1.04) and of the composite of cardiac events (HR 1.22; 95% CI: 1.15–1.29) within six-months after the recall.ConclusionsThe national valsartan recall and subsequent shortage had negative consequences for patients with hypertension. As the threat of shortages increases for drugs that treat common outpatient conditions, systems at the local- and national-levels need to be strengthened to protect patients from drug shortages by providing them with safe and reliable alternatives.
Magnetic voluntary head-fixation in transgenic rats enables lifetime imaging of hippocampal neurons
Authors: Rich P. D. , Thiberge S. Y. , Scott B. B. , Guo C. , Tervo D. G. , Brody C. D. , Karpova A. Y. , Daw N. D. , Tank D. W. 
Published: August 2023

AbstractThe precise neural mechanisms within the brain that contribute to the remarkable lifetime persistence of memory remain unknown. Existing techniques to record neurons in animals are either unsuitable for longitudinal recording from the same cells or make it difficult for animals to express their full naturalistic behavioral repertoire. We present a magnetic voluntary head-fixation system that provides stable optical access to the brain during complex behavior. Compared to previous systems that used mechanical restraint, there are no moving parts and animals can engage and disengage entirely at will. This system is failsafe, easy for animals to use and reliable enough to allow long-term experiments to be routinely performed. Together with a novel two-photon fluorescence collection scheme that increases two-photon signal and a transgenic rat line that stably expresses the calcium sensor GCaMP6f in dorsal CA1, we are able to track and record activity from the same hippocampal neurons, during behavior, over a large fraction of animals’ lives.
The isoflavonoid brazilin inhibits viability and cell migration in breast cancer cells
Authors: Hernández-Moreno Alberto , Nava-Tapia Dania A. , Bello-Martínez Jorge , Olea-Flores Monserrat , Hernández-Moreno Tadeo , Zuñiga-Eulogio Miriam D. , Navarro-Tito Napoleón 
Published: August 2023

AbstractBreast cancer is the most common neoplasm diagnosed in women and is the leading cause of cancer death worldwide. In recent years, compounds isolated from natural sources have been proposed as potential molecules in therapy for breast cancer. In this regard, brazilin has been evaluated in various biological sceneries and has shown pharmacological functions, including anticancer and anti-inflammatory activities. Brazilin was obtained fromHaematoxylum brasiletto. The chemical structure was confirmed by spectroscopic data (1H-NMR,13C-NMR). Concerning biological activity, by MTT assays, brazilin showed cytotoxic effects on MCF7 and MDA-MB-231 breast cancer cell lines. Interestingly, brazilin was not toxic in MCF10A non-tumorigenic breast epithelial cells. We also observed morphological changes to a rounded phenotype associated with apoptosis in breast cancer cell lines and decreased cell migration in a dose and time-dependent manner. Byin silicoanalysis, we found that brazilin interacts with JAK1, JAK2, and iNOS, essential molecules driven cell migration and metastasis in cancer. These data suggest that brazilin can potentially be used as an anti-cancer agent in the future.
Machine Learning Models to Interrogate Proteomewide Covalent Ligandabilities Directed at Cysteines
Authors: Liu Ruibin , Clayton Joseph , Shen Mingzhe , Bhatnagar Shubham , Shen Jana 
Published: August 2023

AbstractMachine learning (ML) identification of covalently ligandable sites may accelerate targeted covalent inhibitor design and help expand the druggable proteome space. Here we report the rigorous development and validation of the tree-based models and convolutional neural networks (CNNs) trained on a newly curated database (LigCys3D) of over 1,000 liganded cysteines in nearly 800 proteins represented by over 10,000 three-dimensional structures in the protein data bank. The unseen tests yielded 94% and 93% AUCs (area under the receiver operating characteristic curve) for the tree models and CNNs, respectively. Based on the AlphaFold2 predicted structures, the ML models recapitulated the newly liganded cysteines in the PDB with over 90% recall values. To assist the community of covalent drug discoveries, we report the predicted ligandable cysteines in 392 human kinases and their locations in the sequence-aligned kinase structure including the PH and SH2 domains. Furthermore, we disseminate a searchable online database LigCys3D (https://ligcys.computchem.org/) and a web prediction server DeepCys (https://deepcys.computchem.org/), both of which will be continuously updated and improved by including newly published experimental data. The present work represents a first step towards the ML-led integration of big genome data and structure models to annotate the human proteome space for the next-generation covalent drug discoveries.
Dorsal raphe neurons signal integrated value during multi-attribute decision-making
Authors: Feng Yang-Yang , Bromberg-Martin Ethan S. , Monosov Ilya E. 
Published: August 2023

AbstractThe dorsal raphe nucleus (DRN) is implicated in psychiatric disorders that feature impaired sensitivity to reward amount, impulsivity when facing reward delays, and risk-seeking when grappling with reward uncertainty. However, whether and how DRN neurons signal reward amount, reward delay, and reward uncertainty during multi-attribute value-based decision-making, where subjects consider all these attributes to make a choice, is unclear. We recorded DRN neurons as monkeys chose between offers whose attributes, namely expected reward amount, reward delay, and reward uncertainty, varied independently. Many DRN neurons signaled offer attributes. Remarkably, these neurons commonly integrated offer attributes in a manner that reflected monkeys’ overall preferences for amount, delay, and uncertainty. After decision-making, in response to post-decision feedback, these same neurons signaled signed reward prediction errors, suggesting a broader role in tracking value across task epochs and behavioral contexts. Our data illustrate how DRN participates in integrated value computations, guiding theories of DRN in decision-making and psychiatric disease.
Habitat loss weakens the positive relationship between grassland plant richness and above-ground biomass
Authors: Yan Yongzhi , Jarvie Scott , Zhang Qing 
Published: August 2023

AbstractHabitat loss and fragmentation per se have been shown to be a major threat to global biodiversity and ecosystem function. However, little is known about how habitat loss and fragmentation per se alters the relationship between biodiversity and ecosystem function (BEF relationship) in the natural landscape context. Based on 130 landscapes identified by a stratified random sampling in the agro-pastoral ecotone of northern China, we investigated the effects of landscape context (habitat loss and fragmentation per se) on plant richness, above-ground biomass, and the relationship between them in grassland communities using a structural equation model. We found that habitat loss directly decreased plant richness and hence decreased above-ground biomass, while fragmentation per se directly increased plant richness and hence increased above-ground biomass. Fragmentation per se also directly decreased soil water content and hence decreased above-ground biomass. Meanwhile, habitat loss decreased the magnitude of the positive relationship between plant richness and above-ground biomass by reducing the percentage of grassland specialists in the community, while fragmentation per se had no significant modulating effect on this relationship. These results demonstrate that habitat loss and fragmentation per se have inconsistent effects on biodiversity and ecosystem function, with the BEF relationship being modulated by landscape context. Our findings emphasise that habitat loss rather than fragmentation per se can weaken the positive BEF relationship by decreasing the degree of habitat specialisation of the community.HighlightsBEF relationship is moderated by landscape context in fragmented landscapes.Habitat loss and fragmentation per se have inconsistent effects.Habitat loss can weaken the positive BEF relationship via reducing the percentage of grassland specialists in the community.
Timing dependent synergies between motor cortex and posterior spinal stimulation in humans
Authors: McIntosh James R. , Joiner Evan F. , Goldberg Jacob L. , Greenwald Phoebe , Murray Lynda M. , Thuet Earl , Modik Oleg , Shelkov Evgeny , Lombardi Joseph M. , Sardar Zeeshan M. , Lehman Ronald A. , Chan Andrew K. , Riew K. Daniel , Harel Noam Y. , Virk Michael S. , Mandigo Christopher , Carmel Jason B. 
Published: August 2023

AbstractVolitional movement requires descending input from motor cortex and sensory feedback through the spinal cord. We previously developed a paired brain and spinal electrical stimulation approach in rats that relies on convergence of the descending motor and spinal sensory stimuli in the cervical cord. This approach strengthened sensorimotor circuits and improved volitional movement through associative plasticity. In humans it is not known whether dorsal epidural SCS targeted at the sensorimotor interface or anterior epidural SCS targeted within the motor system is effective at facilitating brain evoked responses. In 59 individuals undergoing elective cervical spine decompression surgery, the motor cortex was stimulated with scalp electrodes and the spinal cord with epidural electrodes while muscle responses were recorded in arm and leg muscles. Spinal electrodes were placed either posteriorly or anteriorly, and the interval between cortex and spinal cord stimulation was varied. Pairing stimulation between the motor cortex and spinal sensory (posterior) but not spinal motor (anterior) stimulation produced motor evoked potentials that were over five times larger than brain stimulation alone. This strong augmentation occurred only when descending motor and spinal afferent stimuli were timed to converge in the spinal cord. Paired stimulation also increased the selectivity of muscle responses relative to unpaired brain or spinal cord stimulation. Finally, paired stimulation effects were present regardless of the severity of myelopathy as measured by clinical signs or spinal cord imaging. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation.
Microsoft Bing outperforms five other generative artificial intelligence chatbots in the Antwerp University multiple choice medical license exam
Authors: Morreel Stefan , Verhoeven Veronique , Mathysen Danny 
Published: August 2023

AbstractRecently developed chatbots based on large language models (further called bots) have promising features which could facilitate medical education. Several bots are freely available, but their proficiency has been insufficiently evaluated. In this study the authors have tested the current performance on the multiple-choice medical licensing exam of University of Antwerp (Belgium) of six widely used bots: ChatGPT (OpenAI), Bard (Google), New Bing (Microsoft), Claude instant (Anthropic), Claude+ (Anthropic) and GPT-4 (OpenAI). The primary outcome was the performance on the exam expressed as a proportion of correct answers. Secondary analyses were done for a variety of features in the exam questions: easy versus difficult questions, grammatically positive versus negative questions, and clinical vignettes versus theoretical questions. Reasoning errors and untruthful statements (hallucinations) in the bots’ answers were examined. All bots passed the exam; Bing and GPT-4 (both 76% correct answers) outperformed the other bots (62-67%, p= 0.03) and students (61%). Bots performed worse on difficult questions (62%, p= 0.06), but outperformed students (32%) on those questions even more (p<0.01). Hallucinations were found in 7% of Bing’s and GPT4’s answers, significantly lower than Bard (22%, p<0.01) and Claude Instant (19%, p=0.02). Although the creators of all bots try to some extent to avoid their bots being used as a medical doctor, none of the tested bots succeeded as none refused to answer all clinical case questions.Bing was able to detect weak or ambiguous exam questions. Bots could be used as a time efficient tool to improve the quality of a multiple-choice exam.Author SummaryArtificial chatbots such as ChatGPT have recently gained a lot of attention. They can pass exams for medical doctors, sometimes they even perform better than regular students. In this study, we have tested ChatGPT and five other (newer) chatbots in the multiple-choice exam that students in Antwerp (Belgium) must pass to obtain the degree of medical doctor. All bots passed the exam with results similar or better than the students. Microsoft Bing scored the best of all tested bots but still produces hallucinations (untruthful statements or reasoning errors) in seven percent of the answers. Bots performed worse on difficult questions but they outperformed students on those questions even more. Maybe they are most useful when humans don’t know the answer themselves? The creators of the bots try to some extent to avoid their bots being used as a medical doctor, none of the tested bots succeeded as none refused to answer all clinical case questions. Microsoft Bing also turns out to be useful to find weak questions and as such improve the exam.
A phase 2 open-label clinical trial to determine the effect of Famciclovir on Epstein-Barr virus activity as measured by EBV shedding in the saliva of patients with Multiple Sclerosis
Authors: Dobson Ruth , Holden David , Vickaryous Nicola , Bestwick Jonathan , George Katila , Sayali Tatiana , Bianchi Lucia , Wafa Mohammad , Gold Julian , Giovannoni Gavin 
Published: August 2023

AbstractBackgroundThere is increasing evidence that Epstein-Barr virus (EBV) plays a causal role in MS. No treatments have been shown to reduce EBV turnover. We studied the effect of famciclovir on salivary EBV shedding in people with MS (NCT05283551).MethodsPeople with MS receiving natalizumab provided weekly saliva samples for 12 weeks before starting Famciclovir 500mg bd. 12 saliva samples were provided on treatment and 12 following treatment. A real-time quantitative PCR Taqman assay targeted to a non-repeated sequence of the EBV polymerase gene was used to detect EBV DNA in saliva. The proportion of saliva samples containing EBV DNA was compared using the Friedman test.Results30 patients were recruited (19F; mean age 41 years; median EDSS 3.5). 29 patients received famciclovir, 24 completed the 12-week course. 21 participants provided at least one usable saliva sample in all 3 epochs. 10/21 participants had shedding in at least one sample pre-drug; 7/21 when taking famciclovir (not significant). No difference in EBV DNA copy number was seen. There were no drug-related serious adverse events.ConclusionsNo significant effect of famciclovir on EBV shedding was seen. Salivary EBV shedding in this natalizumab-treated cohort was lower than in previous studies; this requires replication.
Lived experience co-design of self-harm interventions: A scoping review
Authors: Wright Lucy C. , Chemas Natalia , Cooper Claudia 
Published: August 2023

ABSTRACTBackgroundSelf-harm prevalence is rising, yet service users encounter stigmatising attitudes and feel let down when they seek professional help. Co-design activities can potentially enable development of more acceptable and effective services.ObjectivesTo map existing literature describing how people with lived experience of self-harm have engaged in co-designing self-harm interventions, understand barriers and facilitators to this engagement and how meaningfulness of co-design has been evaluated.Inclusion criteriaStudies where individuals with lived experience of self-harm (first-hand or carer) have co-designed self-harm interventions.MethodsIn accordance with Joanna Briggs Institute (JBI) scoping review methodology we scoped PubMed, Embase, PsycINFO, Web of Science, Cochrane Library, PROSPERO,ClinicalTrials.govand relevant websites on 24.12.22. A protocol was published online (http://dx.doi.org/10.17605/OSF.IO/P52UD). Results were screened at title and abstract level, then full-text level by two researchers independently. Pre-specified data was extracted, charted, and sorted into themes.ResultsWe included twenty co-designed interventions across mobile health, educational settings, prisons, and emergency departments. Involvement varied from designing content to multi-stage involvement in planning, delivery, and dissemination. Included papers described the contribution of 110 female and 26 male co-designers. Few contributors identified as from a minoritized ethnic or LGBTQ+ group. Six studies evaluated how meaningfully people with lived experience were engaged in co-design: by documenting the impact of contributions on intervention design, or through post-design reflections. Barriers included difficulties recruiting inclusively, making time for meaningful engagement in stretched services, and safeguarding concerns for co-designers. Explicit processes for ensuring safety and wellbeing, flexible schedules, and adequate funding facilitated co-design.ConclusionsTo realise the potential of co-design to improve self-harm interventions, people with lived experience must be representative of those who use services. This requires processes that reassure potential contributors and referrers that co-designers will be safeguarded, remunerated, and their contributions used and valued.ARTICLE SUMMARYStrengths and limitations of this studyComprehensive search strategy with no restriction on publication date to capture breadth of evidenceAll papers screened at title/abstract and full-text level by two researchers independentlyProtocol uploaded to the Open Science Framework prior to conducting scoping reviewDid not check all published self-harm intervention papers for evidence of co-design, so instances where co-design was not mentioned in the title or abstract could have been missedOnly the development paper for each intervention was included – follow up papers were excluded at full-text level which may have overlooked additional co-design details