Miracle-dz/UniFAR-FTUs huggingface dataset:
Antagonism of Propofol Anesthesia by Alkyl-fluorobenzene Derivatives

Despite their frequent use across many clinical settings, general anesthetics are medications with lethal side effects and no reversal agents. A fluorinated analogue of propofol has previously been shown to antagonize propofol anesthesia in tadpoles and zebrafish, but little further investigation of this class of molecules as anesthetic antagonists has been conducted. A 13-member library of alkyl-fluorobenzene derivatives was tested in an established behavioral model of anesthesia in zebrafish at 5 days post fertilization. These compounds were examined for their ability to antagonize propofol and two volatile anesthetics, as well as their binding to the anesthetic-binding model protein apoferritin. The two compounds demonstrating highest antagonistic potency were found to bind apoferritin in a manner similar to propofol. Selected compounds did not show antagonism of volatile anesthetics, indicating some selectivity of this antagonism. Similarities in structure and binding to apoferritin as well as a Schild analysis are suggestive of competitive antagonism, but like the anesthetics, the potential mechanism(s) of these antagonists will require further mechanistic investigation.
Covid19Vaxplorer: a free, online, user-friendly COVID-19 Vaccine Allocation Comparison Tool

Background There are many COVID-19 vaccines currently available, however, Lowand middle-income countries (LMIC) still have large proportions of their populations unvaccinated. Decision-makers need to take decisions as of how best to allocate available vaccine (e.g. boosters or primary series vaccination, which age groups to target) but LMIC often lack the resources to undergo quantitative analyses of vaccine allocation, resulting and ad-hoc policies. We developed Covid19Vaxplorer (https://covid19vaxplorer.fredhutch.org/), a free, user-friendly online tool that simulates region-specific COVID-19 epidemics in conjunction with vaccination. Methods We developed an age-structured mathematical model of SARS-CoV-2 transmission and COVID-19 vaccination. The model considers vaccination with up to three different vaccine products, primary series and boosters. We simulate partial immunity derived from waning of natural infection and vaccination. The model is embedded in an an online tool that allows users in 183 regions in the world to compare several vaccination strategies simultaneously, adjusting parameters to their local epidemics, infrastructure and logistics, and reports cumulative number of deaths and epidemic curves. Results We provide two usage examples of Covid19Vaxplorer for vaccine allocation in Haiti and Afghanistan, which had as of Spring 2023 2% and 33% of their populations vaccinated, and show that in these examples, giving primary series vaccinations prevents more deaths than boosters. Covid19Vaxplorer is an online, free, user-friendly tool that facilitates evidence-based decision making for vaccine distribution.
Is near-infrared spectroscopy a promising predictor for early intracranial hemorrhage diagnosis in the Emergency Department?

Intracranial hemorrhage (ICH) is a serious medical condition that can lead to significant morbidity and mortality if not diagnosed and treated promptly. Early detection and treatment are essential for improving the outcome in patients with ICH. Near-infrared spectroscopy (NIRS) is a non-invasive imaging technique that has been used to detect changes in brain tissue oxygenation and blood flow in various conditions. The aim of this study was to investigate the predictive potential of NIRS for early diagnosis of ICH in patients presenting to the Emergency Department (ED) triage with headache. A total of 378 patients were included in the study. According to the final diagnosis of the patients, 4 groups were formed: migraine, tension-cluster headache, intracranial hemorrhage and intracranial mass, and control group. Cerebral NIRS values “rSO2” were measured at the first professional medical contact with the patient. The right and left rSO2 (RrSO2, LrSO2) were significantly lower and the rSO2 difference was significantly higher in the intracranial hemorrhage group compared to all other patient groups (P<0.001). The cut-off values determined in the receiver operating characteristics (ROC) analysis were RrSO2 ≤67, LrSO2 ≤67, and ΔrSO2 ≥9. This study found that a difference of more than 9 in cerebral right-left NIRS values can be a non-invasive, easy-to-administer, rapid, and reliable diagnostic test for early detection of intracranial bleeding. NIRS holds promise as an objective method in ED triage for patients with intracranial hemorrhage. However, further research is needed to fully understand the potential benefits and limitations of this method.
Preclinical Activity of Two Paclitaxel Nanoparticle Formulations After Intraperitoneal Administration in Ovarian Cancer Murine Xenografts

Background Epithelial ovarian cancer is associated with high mortality due to diagnosis at later stages associated with peritoneal involvement. Several trials have evaluated the effect of intraperitoneal treatment. In this preclinical study, we report the efficacy, pharmacokinetics and pharmacodynamics of intraperitoneal treatment with two approved nanomolecular formulations of paclitaxel (nab-PTX and mic-PTX) in a murine ovarian cancer xenograft model. Methods IC50 was determined in vitro on three ovarian cancer cell lines (OVCAR-3, SK-OV-3 and SK-OV-3-Luc IP1). EOC xenografts were achieved using a modified subperitoneal implantation technique. Drug treatment was initiated 2 weeks after engraftment, and tumor volume and survival were assessed. Pharmacokinetics and drug distribution effects were assessed using UHPLC-MS/MS and MALDI imaging mass spectrometry, respectively. Pharmacodynamic effects were analyzed using immunohistochemistry and transmission electron microscopy using standard protocols. Results We demonstrated sub-micromolar IC50 concentrations for both formulations on three EOC cancer cell lines in vitro. Furthermore, IP administration of nab-PTX or mic-PTX lead to more than 2-fold longer survival compared to a control treatment of IP saline administration (30 days in controls, 66 days in nab-PTX treated animals, and 76 days in mic-PTX animals, respectively). We observed higher tissue uptake of drug following nab-PTX administration when compared to mic-PTX, with highest uptake after 4 hours post-treatment, and confirmed this lower uptake of mic-PTX using HPLC on digested tumor samples. Furthermore, apoptosis was not increased in tumor implants up to 24h post-treatment. Conclusion Intraperitoneal administration of both nab-PTX and mic-PTX results in a significant anticancer efficacy and survival benefit in a mouse OC xenograft model.
Recent Advancements in Reducing the Off-Target Effect of CRISPR-Cas9 Genome Editing

Abstract The CRISPR-Cas (Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)) and the associated protein (Cas9) system, a young but well-studied genome-editing tool, holds plausible solutions to a wide range of genetic disorders. The single-guide RNA (sgRNA) with a 20-base user-defined spacer sequence and the Cas9 endonuclease form the core of the CRISPR-Cas9 system. This sgRNA can direct the Cas9 nuclease to any genomic region that includes a protospacer adjacent motif (PAM) just downstream and matches the spacer sequence. The current challenge in the clinical applications of CRISPR-Cas9 genome-editing technology is the potential off-target effects that can cause DNA cleavage at the incorrect sites. Off-target genome editing confuses and diminishes the therapeutic potential of CRISPR-Cas9 in addition to potentially casting doubt on scientific findings regarding the activities of genes. In this review, we summarize the recent technological advancements in reducing the off-target effect of CRISPR-Cas9 genome editing.
Dietary intake and visceral adiposity in older adults: The Multiethnic Cohort Adiposity Phenotype study

Abstract Background There are established links between the accumulation of body fat as visceral adipose tissue (VAT) and the risk of developing obesity‐associated metabolic disease. Previous studies have suggested that levels of intake of specific foods and nutrients are associated with VAT accumulation after accounting for total energy intake. Objective This study assessed associations between a priori selected dietary factors on VAT quantified using abdominal magnetic resonance imaging. Methods The cross‐sectional Multiethnic Cohort Adiposity Phenotype Study included n = 395 White, n = 274 Black, n = 269 Native Hawaiian, n = 425 Japanese American and n = 358 Latino participants (mean age = 69 years ± 3 SD). Participants were enrolled stratified on sex, race, ethnicity and body mass index. General linear models were used to estimate the mean VAT area (cm2) for participants categorized into quartiles based on their dietary intake of selected foods/nutrients adjusting for age, sex, racial and ethnic groups, the total percentage fat from whole‐body dual energy X‐ray absorptiometry and total energy. Results There were significant inverse associations with VAT for dietary intake of total vegetables, total fruits (including juice), cereals, whole grains, calcium, copper and dietary fiber (p‐trend ≤0.04). Positive trends were observed for VAT for participants who reported higher intake of potatoes, total fat and saturated fatty acids (SFA) (p‐trend ≤0.02). Foods/nutrients that met the multiple testing significance threshold were total fruits, whole grains, copper, dietary fiber and SFA intake. Conclusions These results highlight foods and nutrients including SFA, total fruit, whole grains, fiber and copper as potential candidates for future research to inform dietary guidelines for the prevention of chronic disease among older adults.
A Targeted Multi-Crystalline Manganese Oxide as a Tumor-Selective Nano-Sized MRI Contrast Agent for Early and Accurate Diagnosis of Tumors

Introduction Magnetic resonance imaging (MRI) is an important tool for the accurate diagnosis of malignant tumors in clinical settings. However, the lack of tumor-specific MRI contrast agents limits diagnostic accuracy. Methods Herein, we developed αv integrin receptor-targeting multi-crystalline manganese oxide (MCMO) as a novel MRI contrast agent for accurate diagnosis of tumors by coupling iRGD cyclopeptide PEGylation polymer onto the surface of MCMO (iRGD-pMCMO). Results The MCMO consisted of numerous small crystals and exhibited an oval structure of 200 nm in size. The iRGD-pMCMO actively recognizes tumor cells and effectively accumulates at the tumor site, consequently releasing abundant Mn2+ ions in a weakly acidic and high-GSH-expressing tumor microenvironment. Subsequently, Mn2+ ions interact with cellular GSH to form Mn-GSH chelates, enabling efficient T1-weighted MR contrast imaging. In vivo experiments indicated that iRGD-pMCMO significantly improved T1-weighted images, achieving an accurate diagnosis of subcutaneous and orthotopic tumors. The results verified that the T1 contrast effect of iRGD-pMCMO was closely associated with the expression of GSH in tumor cells. Conclusion Altogether, the novel tumor-targeting, highly sensitive MRI contrast agent developed in this study can improve the accuracy of MRI for tumor diagnosis.
Relationship Between Liver Fibrosis and Increased Risk of Symptomatic Intracranial Hemorrhage in Ischemic Stroke Patients Undergoing Mechanical Thrombectomy

Background Liver fibrosis has been reported to be associated with hematoma expansion and mortality in patients with intracerebral hemorrhage. This study aimed to detect the association between liver fibrosis and symptomatic intracranial hemorrhage (sICH) in ischemic stroke after mechanical thrombectomy (MT). Methods We retrospectively included patients with large artery occlusion in the anterior circulation and treated with MT at a single stroke center. The fibrosis-4 index (FIB-4) was used to assess the severity of liver fibrosis. sICH was diagnosed according to the Heidelberg Bleeding Classification criteria. Multivariate logistic regression and restricted cubic spline analysis were conducted to examine the relationship between liver fibrosis and sICH. Results Among the 578 patients (mean age, 70.1 years; 58.5% male) included in the study, 65 (11.2%) individuals were diagnosed with sICH. After adjusting for demographic characteristics and other potential confounders, a higher FIB-4 index was found to be independently associated with an increased risk of sICH (odds ratio: 1.306, 95% confidence interval: 1.127–1.512, P=0.001). Similar results were obtained when analyzing FIB-4 as a categorical variable. Conclusion This study demonstrated that there is a significant association between FIB-4 and the risk of sICH in patients with acute ischemic stroke who underwent MT. Therefore, liver fibrosis could serve as a valuable parameter in monitoring the risk of sICH following MT.
A previously undescribed scene-selective site is the key to encoding ego-motion in naturalistic environments

Current models of scene processing in the human brain include three scene-selective areas: the Parahippocampal Place Area (or the temporal place areas; PPA/TPA), the restrosplenial cortex (or the medial place area; RSC/MPA) and the transverse occipital sulcus (or the occipital place area; TOS/OPA). Here, we challenged this model by showing that at least one other scene-selective site can also be detected within the human posterior intraparietal gyrus. Despite the smaller size of this site compared to the other scene-selective areas, the posterior intraparietal gyrus scene-selective (PIGS) site was detected consistently in a large pool of subjects (n=59; 33 females). The reproducibility of this finding was tested based on multiple criteria, including comparing the results across sessions, utilizing different scanners (3T and 7T) and stimulus sets. Furthermore, we found that this site (but not the other three scene-selective areas) is significantly sensitive to ego-motion in scenes, thus distinguishing the role of PIGS in scene perception relative to other scene-selective areas. These results highlight the importance of including finer scale scene-selective sites in models of scene processing – a crucial step toward a more comprehensive understanding of how scenes are encoded under dynamic conditions.
Gamification in Critical Care Education and Practice

OBJECTIVES: To explore gamification as an alternative approach to healthcare education and its potential applications to critical care. DATA SOURCES: English language manuscripts addressing: 1) gamification theory and application in healthcare and critical care and 2) implementation science focused on the knowledge-to-practice gap were identified in Medline and PubMed databases (inception to 2023). STUDY SELECTION: Studies delineating gamification underpinnings, application in education or procedural mentoring, utilization for healthcare or critical care education and practice, and analyses of benefits or pitfalls in comparison to other educational or behavioral modification approaches. DATA EXTRACTION: Data indicated the key gamification tenets and the venues within which they were used to enhance knowledge, support continuing medical education, teach procedural skills, enhance decision-making, or modify behavior. DATA SYNTHESIS: Gamification engages learners in a visual and cognitive fashion using competitive approaches to enhance acquiring new knowledge or skills. While gamification may be used in a variety of settings, specific design elements may relate to the learning environment or learner styles. Additionally, solo and group gamification approaches demonstrate success and leverage adult learning theory elements in a low-stress and low-risk setting. The potential for gamification-driven behavioral modification to close the knowledge-to-practice gap and enable guideline and protocol compliance remains underutilized. CONCLUSIONS: Gamification offers the potential to substantially enhance how critical care professionals acquire and then implement new knowledge in a fashion that is more engaging and rewarding than traditional approaches. Accordingly, educational undertakings from courses to offerings at medical professional meetings may benefit from being gamified.
Intensive glucose control in critically ill adults: a protocol for a systematic review and individual patient data meta-analysis

Objective The optimal target for blood glucose concentration in critically ill patients is unclear. We will perform a systematic review and meta-analysis with aggregated and individual patient data from randomized controlled trials, comparing intensive glucose control with liberal glucose control in critically ill adults. Data sources MEDLINE®, Embase, the Cochrane Central Register of Clinical Trials, and clinical trials registries (World Health Organization, clinical trials.gov). The authors of eligible trials will be invited to provide individual patient data. Published trial-level data from eligible trials that are not at high risk of bias will be included in an aggregated data meta-analysis if individual patient data are not available. Methods Inclusion criteria: randomized controlled trials that recruited adult patients, targeting a blood glucose of ≤ 120mg/dL (≤ 6.6mmol/L) compared to a higher blood glucose concentration target using intravenous insulin in both groups. Excluded studies: those with an upper limit blood glucose target in the intervention group of > 120mg/dL (> 6.6mmol/L), or where intensive glucose control was only performed in the intraoperative period, and those where loss to follow-up exceeded 10% by hospital discharge. Primary endpoint In-hospital mortality during index hospital admission. Secondary endpoints: mortality and survival at other timepoints, duration of invasive mechanical ventilation, vasoactive agents, and renal replacement therapy. A random effect Bayesian meta-analysis and hierarchical Bayesian models for individual patient data will be used. Discussion This systematic review with aggregate and individual patient data will address the clinical question, ‘what is the best blood glucose target for critically ill patients overall? ’ Protocol version 0.4 - 06/26/2023 PROSPERO registration: CRD42021278869
HABITAT USE BY INVASIVE NORTH AMERICAN BEAVER DURING INTERMEDIATE AND LONG-TERM COLONIZATION PERIODS IN SOUTHERN PATAGONIA

Since their introduction to southern Patagonia in 1946, North American beavers (Castor canadensis) have become a major impact to streams and forests. Scientists and managers now call for their eradication, requiring research to orient actions. John et al. (2010) showed that predicting beaver presence, which is crucial to plan eradication efforts, varies throughout colonization time (initial = unpredictable occupation of random sites; intermediate = predictable occupation of optimal sites; long-term = unpredictable occupation of sub-optimal loca- tions). Beaver presence/absence and habitat variables (geomorphology, soil, and vegetation) were measured in the field and from satellite images in sites colonized at intermediate (Brunswick Peninsula ~1994) and long-term (Navarino Island ~1960) periods to predict this species' habitat use. Habitat suitability models were constructed using generalized linear models with those variables significantly different between sites with and without beaver. As hypothesized, a significant explanatory habitat model could not be developed for long-term occupa - tion sites. However, beaver presence was predictable at intermediate colonization sites, and the best significant model included only river sinuosity and explained 74% of data variability. The model suggested that beavers used areas with greater river sinuosity, which could be measured from satellite images. Since remotely-sensed information requires less field effort, this approach could be useful in southern Patagonia's remote areas, where access is difficult. Additionally, these findings highlight the overall difficulty of planning a large-scale beaver eradication program and predicting beaver habitat use across a gradient of habitat types and colonization stages.
Implication of lncRNA MSTRG.81401 in Hippocampal Pyroptosis Induced by P2X7 Receptor in Type 2 Diabetic Rats with Neuropathic Pain Combined with Depression

Major depressive disorder (MDD) is a common complication of diabetes and is often observed alongside diabetic neuropathic pain (DNP) as a comorbidity in diabetic patients. Long non-coding RNA (lncRNA) plays an important role in various pathophysiological processes. The P2X7 receptor is responsible for triggering inflammatory responses, such as pyroptosis, linked to pain and depression. The aim of this study was to investigate the effect of lncRNA MSTRG.81401 on hippocampal pyroptosis induced by the P2X7 receptor in diabetic rats with DNP combined with MDD (DNP + MDD). Our results showed that the expression of lncRNA MSTRG.81401 was significantly elevated in the hippocampus of DNP + MDD rats compared with the control group. Following the administration of shRNA targeting lncRNA MSTRG.81401, a notable elevation in mechanical and thermal pain thresholds was observed in rats with comorbid DNP and MDD. Additionally, significant improvements in depression-like behaviors were evident in the open-field test (OFT), sucrose preference test (SPT), and forced swim test (FST). In the DNP + MDD rats, elevated levels in hippocampal P2X7 receptor mRNA and protein were observed, along with increased co-expression of P2X7 and the astrocytic marker glial fibrillary acidic protein (GFAP). Meanwhile, in DNP + MDD rats, the heightened mRNA expression of NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), pyroptosis-related protein Gasdermin D (GSDMD), caspase-1, IL-1β, IL-18, and TNF-α was detected, in addition to increased serum levels of IL-1β, IL-18 and TNF-α. After shRNA treatment with lncRNA MSTRG.81401, the above abnormal changes in indicators for pyroptosis and inflammation were improved. Therefore, our study demonstrates that shRNA of lncRNA MSTRG.81401 can alleviate the pain and depression-like behaviors in diabetic rats associated with the comorbidity of DNP and MDD by inhibiting the hippocampal P2X7 receptor-mediated pyroptosis pathway and pro-inflammatory responses. This suggests that the P2X7R/NLRP3/caspase-1 implicated pyroptosis and inflammatory scenario may serve as a potential target for the management of comorbid DNP and MDD in diabetes.
Multitasking Pharmacophores Support Cabotegravir-Based Long-Acting HIV Pre-Exposure Prophylaxis (PrEP)

Cabotegravir is an integrase strand transfer inhibitor (INSTI) for HIV treatment and prevention. Cabotegravir-based long-acting pre-exposure prophylaxis (PrEP) presents an emerging paradigm for infectious disease control. In this scheme, a combination of a high efficacy and low solubility of anti-infection drugs permits the establishment of a pharmaceutical firewall in HIV-vulnerable groups over a long period. Although the structure-activity-relationship (SAR) of cabotegravir as an INSTI is known, the structural determinants of its low solubility have not been identified. In this work, we have integrated multiple experimental and computational methods, namely X-ray diffraction, solid-state NMR (SSNMR) spectroscopy, solution NMR spectroscopy, automated fragmentation (AF)-QM/MM and density functional theory (DFT) calculations, to address this question. The molecular organization of cabotegravir in crystal lattice has been determined. The combination of very-fast magic-angle-sample-spinning (VF MAS) SSNMR and solution NMR, as supported by AF-QM/MM and DFT calculations, permits the identification of structural factors that contribute to the low aqueous solubility of cabotegravir. Our study reveals the multitasking nature of pharmacophores in cabotegravir, which controls the drug solubility and, meanwhile, the biological activity. By unraveling these function-defining molecular features, our work could inspire further development of long-acting HIV PrEP drugs.