Long-distance Southern Ocean environmental DNA (eDNA) transect provides insights into spatial marine biota and invasion pathways for non-native species.

The Southern Ocean surrounding Antarctica harbours some of the most pristine marine environments remaining, but is increasingly vulnerable to anthropogenic pressures, climate change, and invasion by non-native species. Monitoring biotic responses to cumulative impacts requires temporal and spatial baselines and ongoing monitoring - traditionally, this has been obtained by continuous plankton recorder (CPR) surveys. Here, we conduct one of the longest environmental DNA (eDNA) transects yet, spanning over 3000 nautical miles from Hobart (Australia) to Davis Station (Antarctica). We evaluate eDNA sampling strategies for long-term open ocean biomonitoring by comparing two water volume and filter pore size combinations: large (12 L with 20 µm) and small (2 L with 0.45 µm). Employing a broad COI metabarcoding assay, we found the large sample/pore combination was better suited to open-ocean monitoring, detecting more target DNA and rare or low abundance species. Comparisons with four simultaneously conducted CPR transects revealed that eDNA detections were more diverse than CPR, with 7 (4 unique) and 4 (1 unique) phyla detections respectively. While both methods effectively delineated biodiversity patterns across the Southern Ocean, eDNA enables surveys in the presence of sea-ice where CPR cannot be conducted. Accordingly, 16 species of concern were detected along the transect using eDNA, notably in the Antarctic region (south of 60°S). These were largely attributed to hull biofouling, a recognized pathway for marine introductions into Antarctica. Given the vulnerability of Antarctic environments to potential introductions in a warming Southern Ocean, this work underscores the importance of continued biosecurity vigilance. We advocate integrating eDNA metabarcoding with long-term CPR surveys in the Southern Ocean, emphasising the urgency of its implementation. We anticipate temporal and spatial interweaving of CPR, eDNA, and biophysical data will generate a more nuanced picture of Southern Ocean ecosystems, with significant implications for the conservation and preservation of Antarctic ecosystems.

APOLLOE4 Phase 3 study of oral ALZ-801/valiltramiprosate in APOE ε4/ε4 homozygotes with early Alzheimer's disease: Trial design and baseline characteristics.

INTRODUCTION: The approved amyloid antibodies for early Alzheimer's disease (AD) carry a boxed warning about the risk of amyloid-related imaging abnormalities (ARIAs) that are highest in apolipoprotein E (APOE) ε4/ε4 homozygotes. ALZ-801/valiltramiprosate, an oral brain-penetrant amyloid beta oligomer inhibitor is being evaluated in APOE ε4/ε4 homozygotes with early AD. METHODS: This Phase 3 randomized, double-blind, placebo-controlled, 78-week study of ALZ-801 administered as 265 mg twice per day tablets, enrolled 50- to 80-year-old homozygotes with Mini-Mental State Examination (MMSE) ≥ 22 and Clinical Dementia Rating-Global Score 0.5 or 1.0. The study is powered to detect a 2.0 to 2.5 drug-placebo difference on the Alzheimer's Disease Assessment Scale 13-item Cognitive subscale primary outcome with 150 subjects/arm. The key secondary outcomes are Clinical Dementia Rating-Sum of Boxes and Instrumental Activities of Daily Living; volumetric magnetic resonance imaging and fluid biomarkers are additional outcomes. RESULTS: The APOLLOE4 Phase 3 trial enrolled 325 subjects with a mean age of 69 years, 51% female, MMSE 25.6, and 65% mild cognitive impairment. Topline results are expected in 2024. DISCUSSION: APOLLOE4 is the first disease-modification AD trial focused on APOE ε4/ε4 homozygotes. Oral ALZ-801 has the potential to be the first effective and safe anti-amyloid treatment for the high-risk APOE ε4/ε4 population. Highlights: The APOLLOE4 Phase 3, placebo-controlled, 78-week study is designed to evaluate the efficacy and safety of ALZ-801 265 mg twice per day in early Alzheimer's disease (AD) subjects with the apolipoprotein E (APOE) ε4/ε4 genotype.The enrolled early AD population (N = 325) has 51% females, a mean age = 69 years, and a mean Mini-Mental State Examination = 25.6, with the majority being mild cognitive impairment subjects, a similar disease stage to the lecanemab Phase 3 AD trial (Clarity AD).The primary outcome is the cognitive Alzheimer's Disease Assessment Scale 13-item Cognitive subscale, with two functional measures as key secondary outcomes (Clinical Dementia Rating-Sum of Boxes, Amsterdam-Instrumental Activities of Daily Living), and with hippocampal volume and fluid biomarkers as additional outcomes.The study is unique in allowing a large number of microhemorrhages or siderosis at baseline magnetic resonance imaging, lesions that indicate concomitant cerebral amyloid angiopathy (CAA).At baseline, 32% of the enrolled population had at least 1 microhemorrhage, 24% had 1 to 4, and 8% had > 4 microhemorrhages; 10% had at least 1 siderosis lesion; with more males than females having microhemorrhages (63% vs. 37%) and siderosis (68% vs. 32%).Study results will become available in the second half of 2024 and, if positive, ALZ-801 may become the first oral drug to demonstrate a favorable benefit/risk profile in APOE ε4/ε4 AD subjects.

Assessing inoculation's effectiveness in motivating resistance to conspiracy propaganda in Finnish and United States samples.

Introduction: This study tested the motivational power of inoculation to foster resistance to conspiracy propaganda (9/11 Truth Movement), comparing inoculation effects across United States and Finnish study participants. Method: We used a 2 inoculation (treatment vs. control) × 2 national culture (American vs. Finnish) independent groups design (N = 319), while examining the effects of motivational threat and thinking modes-analytic vs. intuitive-on the inoculation process. To test the effectiveness of the inoculation strategy, we used an excerpt from a conspiracy film Loose Change as a counterattitudinal attack message. Results: Our results indicated that inoculation was effective at motivating resistance regardless of national culture. Inoculation effects emerged mostly as a direct effect on resistance and two indirect effects wherein motivational threat mediated the relationship between inoculation and resistance as well as inoculation and analytic mode of message processing. Although we found that an increase in analytic mode of processing facilitated resistance and intuitive processing increased conspiracy-theory endorsement, the indirect effects between inoculation and resistance via message processing modes were not significant. Finally, the data revealed national culture differences in analytic mode and cultural-context differences mostly pertaining to the relationships between thinking styles, media literacy, and modes of thinking. Discussion: These results offer important theoretical implications for inoculation scholarship and suggest viable practical solutions for efforts to mitigate misinformation and conspiratorial beliefs.

Regulatory Pathways for Qualification and Acceptance of Digital Health Technology-Derived Clinical Trial Endpoints: Considerations for Sponsors.

Despite widespread interest and substantial investment in the adoption of sensor-based digital health technologies (sDHTs) for remote data capture in drug development trials, no drug has been approved based on an sDHT-derived primary endpoint in the United States (US). One reason for this lack of advancement is the complexity of obtaining regulatory endorsement for those endpoints within current US regulatory pathways. The goal of our review is to describe the two choices currently available to pharmaceutical study Sponsors: (i) they may navigate the traditional route of compiling the evidence to support the sDHT-derived endpoint in their investigational new drug (IND) application, requiring specific expertise and substantial resources; or (ii) they may navigate the drug development tool (DDT) pathway with the goal of qualifying their sDHT-derived endpoint as a biomarker or clinical outcome assessment applicable to a broader context of use (COU), either alone or as part of a partnership or consortium. We describe the nuances of each pathway; the evidentiary requirements for supporting an sDHT-derived endpoint and the technology used to capture it; and the impact that an sDHT's regulatory status may have on a Sponsor's decision to use it for data capture. By systematically comparing the IND and DDT pathways, our over-arching goals are to support the increasing deployment of sDHTs within the clinical research setting and help advance regulatory science in the field of digital medicine.

A spatial atlas of mitochondrial gene expression reveals dynamic translation hubs and remodeling in stress.

Mitochondrial genome expression is important for cellular bioenergetics. How mitochondrial RNA processing and translation are spatially organized across dynamic mitochondrial networks is not well understood. Here, we report that processed mitochondrial RNAs are consolidated with mitoribosome components into translation hubs distal to either nucleoids or processing granules in human cells. During stress, these hubs are remodeled into translationally repressed mesoscale bodies containing messenger, ribosomal, and double-stranded RNA. We show that the highly conserved helicase SUV3 contributes to the distribution of processed RNA within mitochondrial networks, and that stress bodies form downstream of proteostatic stress in cells lacking SUV3 unwinding activity. We propose that the spatial organization of nascent chain synthesis into discrete domains serves to throttle the flow of genetic information in stress to ensure mitochondrial quality control.

Development of a Multiparticulate Metal-Organic Framework/Textile Fiber Swatch.

The versatility of metal-organic frameworks (MOFs) has led to groundbreaking applications in a wide variety of fields, especially in the areas of energy, environment, and sustainability. For example, MOFs can be designed for high uptake of toxic gases and pollutants, such as CO2, NH3, and SO2, but designing a single MOF that shows tangible uptake for all of these gases is challenging due to the differences in the chemical and physical properties of these molecules. To this end, integrating multiple MOFs onto textile fibers and crafting various structures have emerged as pivotal developments, enhancing framework durability and usability. MOF composites prepared on readily available textile fibers offer the flexibility essential for critical applications, including heterogeneous catalysis, chemical sensing, toxic gas adsorption, and drug delivery, while preserving the unique characteristics of MOFs. This study introduces a scalable and adaptable method for seamlessly embedding multiple high-performing MOFs onto a single textile fiber using a dip-coating method. We explored the uptake capacity of these multi-MOF composites for CO2, NH3, and SO2 and observed a performance similar to that of traditional powdered materials. Along with harmful gas adsorption, we also have evaluated the permeation and reactivity of these MOF/textile composites toward chemical warfare agents (CWAs) like GD (soman), HD (mustard gas), and VX. In combination, these results demonstrate a fundamental advancement toward establishing a consistent strategy for the hydrolysis of nerve agents in real-world scenarios. This approach can substantially increase the protection toward CWAs and enhance the effectiveness of protective equipment such as fabrics for protective garments. This dip-coating method for the integration of multiple MOFs on a single textile fiber unlocks a wealth of possibilities and paves the way for future innovations in the deployment of MOF-based composites.

Zirconium- 89 Labeled Antibody K1-70 for PET Imaging of Thyroid-stimulating Hormone Receptor Expression in Thyroid Cancer.

PURPOSE: Thyroid-stimulating hormone receptor (TSHR) is a G-protein coupled receptor that is highly expressed on benign and malignant thyroid tissues. TSHR binding and activation has long been a component of thyroid cancer molecular imaging and radiotherapy, by promoting expression of the sodium-iodide symporter (NIS) and incorporation of I-131 into thyroid hormones. Here, we report the radiosynthesis and preclinical evaluation of a Zirconium-89 (89Zr) labeled TSHR antibody to serve as a positron emission tomography (PET) diagnostic correlate for therapeutic agents targeting TSHR without reliance on NIS. PROCEDURES: TSHR human monoclonal antibody K1-70 was conjugated to chelator desferrioxamine-p-benzyl-isothiocyanate, followed by labeling with Zr-89, yielding the radiotracer 89Zr-DFO-TSHR-Ab. The in vitro cellar uptake and binding affinity of 89Zr-DFO-TSHR-Ab were analyzed in three new TSHR stable overexpressing tumor cell lines and their corresponding wild types (WT) with low or no TSHR expression. 89Zr-DFO-TSHR-Ab PET/CT imaging of TSHR expression was evaluated in tumor mouse models bearing one TSHR-positive tumor and other negative control with or without the coinjection of antibody K1-70, and then verified by radiotracer biodistribution study and tumor immunohistochemistry (IHC). RESULTS: The conjugate DFO-TSHR-Ab was labeled with Zr-89 at 37 °C for 60 min and purified by PD-10 column in radiochemical yields of 68.8 ± 9.9%, radiochemical purities of 98.7 ± 0.8%, and specific activities of 19.1 ± 2.7 mCi/mg (n = 5). In vitro cell studies showed 89Zr-DFO-TSHR-Ab had significantly high uptake on TSHR expressing tumor cells with nanomolar affinity and high potency. Preclinical PET/CT imaging revealed that 89Zr-DFO-TSHR-Ab selectively detected TSHR expressing thyroid tumors and displayed improved in vivo performance with the coinjection of unlabeled TSHR antibody K1-70 leading to higher uptake in TSHR expressing tumors than parental WT tumors and physiologic tissues; this observation was confirmed by the biodistribution and immunostaining analyses. CONCLUSIONS: We synthesized 89Zr-labeled antibody K1-70 as a new radiopharmaceutical for PET imaging of TSHR. 89Zr-DFO-TSHR-Ab has high radioactive uptake and retention in TSHR expressing tumors and cleared quickly from most background tissues in mouse models. Our study demonstrated that 89Zr-DFO-TSHR-Ab has the potential for PET imaging of TSHR-positive thyroid cancer and monitoring TSHR-targeted therapy.

Attention and executive functioning in children and adolescents treated for high-risk acute lymphoblastic leukemia: A report from the Children's Oncology Group (COG).

OBJECTIVES: Survivors of childhood B-acute lymphoblastic leukemia (B-ALL) are at risk for difficulties with attention and executive functioning (EF) as a late effect of treatment. The present study aimed to identify treatment and demographic factors associated with risk for difficulties with EF in youth treated for high-risk B-ALL. METHOD: Children and adolescents with B-ALL treated on Children's Oncology Group (COG) protocol AALL0232 were randomized to high-dose or escalating-dose methotrexate (MTX), and either dexamethasone or prednisone during the induction phase. Neuropsychological functioning was evaluated via protocol AALL06N1, including performance-based and parent-report measures, for 177 participants (57% female, 81% white; mean age at diagnosis = 8.4 years; SD = 5.0) 8-24 months following treatment completion. RESULTS: Mean scores for all attention and EF measures were within the average range, with no significant differences as a function of MTX delivery or steroid treatment (all p > 0.05). In multivariable models, participants with US public insurance exhibited significantly greater parent-reported EF difficulties than those with US private or non-US insurance (p ≤ 0.05). Additionally, participants diagnosed under 10 years of age performed significantly more poorly on measures of attention (i.e., continuous performance task, p ≤ 0.05) and EF (i.e., verbal fluency and tower planning task, p ≤ 0.05). CONCLUSIONS: For survivors of pediatric B-ALL, treatment-related factors were not associated with attention or EF outcomes. In contrast, outcomes varied by demographic characteristics, including age and insurance type, an indicator of economic hardship. Future research is needed to more directly assess the contribution of socioeconomic status on cognitive outcomes in survivors.

Avatrombopag for severe refractory thrombocytopenia in a pediatric patient with ALL following allogeneic hematopoietic stem cell transplantation: A case report.

Patients who receive allogeneic hematopoietic stem cell transplantation (alloHSCT) are at risk for developing persistent thrombocytopenia. Here, we describe treatment with avatrombopag, a thrombopoietin receptor agonist, in a pediatric patient with chronic, severe, transfusion-dependent thrombocytopenia (<10 × 103/µL) post-alloHSCT that was persistent despite treatment with romiplostim, another thrombopoietin receptor agonist. Following the granting of a compassionate use investigational new drug authorization, avatrombopag treatment was initiated, and the patient's platelet count increased. To date, the patient has maintained a platelet count >100 × 103/µL. No adverse events or medication toxicities have been reported, and he has resumed his pre-alloHSCT activities.

Reactivity of a triamidoamine terminal uranium(VI)-nitride with 3d-transition metal metallocenes.

Reactions between [(TrenTIPS)UVIN] (1, TrenTIPS = {N(CH2CH2NSiPri3)3}3-) and [MII(η5-C5R5)2] (M/R = Cr/H, Mn/H, Fe/H, Ni/H) were intractable, but M/R = Co/H or Co/Me afforded [(TrenTIPS)UVN-(η1:η4-C5H5)CoI(η5-C5H5)] (2) and [(TrenTIPS)UIV-NH2] (3), respectively. For M/R = V/H [(TrenTIPS)UIV-NVIV(η5-C5H5)2] (4), was isolated. Complexes 2-4 evidence one-/two-electron uranium reductions, nucleophilic nitrides, and partial N-atom transfer.

Investigating the Bone Bruise Patterns in Pediatric Patients With Contact and Noncontact Acute Anterior Cruciate Ligament Tears: A Multicenter Study.

BACKGROUND: In adults with anterior cruciate ligament (ACL) tears, bone bruises on magnetic resonance imaging (MRI) scans provide insight into the underlying mechanism of injury. There is a paucity of literature that has investigated these relationships in children with ACL tears. PURPOSE: To examine and compare the number and location of bone bruises between contact and noncontact ACL tears in pediatric patients. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Boys ≤14 years and girls ≤12 years of age who underwent primary ACL reconstruction surgery between 2018 and 2022 were identified at 3 separate institutions. Eligibility criteria required detailed documentation of the mechanism of injury and MRI performed within 30 days of the initial ACL tear. Patients with congenital lower extremity abnormalities, concomitant fractures, injuries to the posterolateral corner and/or posterior cruciate ligament, previous ipsilateral knee injuries or surgeries, or closed physes evident on MRI scans were excluded. Patients were stratified into 2 groups based on a contact or noncontact mechanism of injury. Preoperative MRI scans were retrospectively reviewed for the presence of bone bruises in the coronal and sagittal planes using fat-suppressed T2-weighted images and a grid-based mapping technique of the tibiofemoral joint. RESULTS: A total of 109 patients were included, with 76 (69.7%) patients sustaining noncontact injuries and 33 (30.3%) patients sustaining contact injuries. There were no significant differences between the contact and noncontact groups in terms of age (11.8 ± 2.0 vs 12.4 ± 1.3 years; P = .12), male sex (90.9% vs 88.2%; P > .99), time from initial injury to MRI (10.3 ± 8.1 vs 10.4 ± 8.9 days; P = .84), the presence of a concomitant medial meniscus tear (18.2% vs 14.5%; P = .62) or lateral meniscus tear (69.7% vs 52.6%; P = .097), and sport-related injuries (82.9% vs 81.8%; P = .89). No significant differences were observed in the frequency of combined lateral tibiofemoral (lateral femoral condyle + lateral tibial plateau) bone bruises (87.9% contact vs 78.9% noncontact; P = .41) or combined medial tibiofemoral (medial femoral condyle [MFC] + medial tibial plateau) bone bruises (54.5% contact vs 35.5% noncontact; P = .064). Patients with contact ACL tears were significantly more likely to have centrally located MFC bruising (odds ratio, 4.3; 95% CI, 1.6-11; P = .0038) and less likely to have bruising on the anterior aspect of the lateral tibial plateau (odds ratio, 0.27; 95% CI, 0.097-0.76; P = .013). CONCLUSION: Children with contact ACL tears were 4 times more likely to present with centrally located MFC bone bruises on preoperative MRI scans compared with children who sustained noncontact ACL tears. Future studies should investigate the relationship between these bone bruise patterns and the potential risk of articular cartilage damage in pediatric patients with contact ACL tears.

Discordant Treatment Goals for Patients With Atrial Fibrillation and Clinical Trials Metrics.

BACKGROUND: Most clinical trials define successful atrial fibrillation (AF) treatment as no AF episodes longer than 30 seconds. Yet, there has been minimal study of how patients define successful treatment and whether their perspectives align with trial outcomes. OBJECTIVES: Survey patients with AF to identify: 1) what aspect of AF is most important to address (frequency, duration, or severity of AF episodes); 2) what AF burden would be considered acceptable to consider treatment successful; and 3) to establish patient preferences for successful treatment thresholds for a validated patient-reported outcome (PRO) score. METHODS: We surveyed patients receiving active care for AF at a single tertiary care center modeled after the Toronto AF Severity Scale (AFSS). The survey consisted of current and "successful treatment" AF frequency, burden, and symptom domains; and baseline socioeconomic information. RESULTS: Of 7,000 invitations, 852 individuals completed the survey (12% response) with a mean age of 65 ± 13 years, 36.5% were female, and they had a mean CHA2DS2-VAsc score of 2.9 ± 1.9. Overall, 114 (13%) selected a decrease in AF episode duration as their top treatment priority, 505 (59%) episode frequency, and 230 (27%) episode severity. Overall, 207 (24%) patients would only consider a treatment successful if they never had AF again, whereas 645 (76%) patients considered success to be fewer AF episodes. A total of 341 (40%) patients would only consider a treatment successful if AF episodes lasted less than a few minutes, whereas 509 (60%) patients would accept AF episodes lasting >30 minutes. An AFSS symptom score ≤5 was considered a good outcome by 80% of respondents. CONCLUSIONS: Patients prioritize decreased AF frequency over improvements in severity or duration, and an AFSS ≤5 would be a reasonable outcome of AF treatment. Most patients would consider treatment successful if they had more than 1 AF episode lasting longer than 30 seconds. Future clinical trial design should consider patients' perspectives when designing outcomes.

Reporting the anti-neuroinflammatory potential of selected spondias mombin flavonoids through network pharmacology and molecular dynamics simulations.

Neuroinflammation plays a pivotal role in the development and progression of neurodegenerative diseases, with a complex interplay between immune responses and brain activity. Understanding this interaction is crucial for identifying therapeutic targets and developing effective treatments. This study aimed to explore the neuroprotective properties of flavonoid compounds from Spondias mombin via the modulation of neuroinflammatory pathway using a comprehensive in-silico approach, including network pharmacology, molecular docking, and dynamic simulations. Active flavonoid ingredients from S. mombin were identified, and their potential protein targets were predicted through Network Pharmacology. Molecular docking was conducted to determine the binding affinities of these compounds against targets obtained from network pharmacology, prioritizing docking scores ≥ - 8.0 kcal/mol. Molecular dynamic simulations (MDS) assessed the stability and interaction profiles of these ligand-protein complexes. The docking study highlighted ≥ - 8.0 kcal/mol for the ligands (catechin and epicatechin) against FYN kinase as a significant target. However, these compounds failed the blood-brain barrier (BBB) permeability test. MDS confirmed the stability of catechin and the reference ligand at the FYN kinase active site, with notable interactions involving hydrogen bonds, hydrophobic contacts, and water bridges. GLU54 emerged as a key residue in the catechin-FYN complex stability due to its prolonged hydrogen bond interaction. The findings underscore the potential of S. mombin flavonoids as therapeutic agents against neuroinflammation, though optimization and nanotechnology-based delivery methods are suggested to enhance drug efficacy and overcome BBB limitations.

Opioid Overdose Patients in Central Missouri, United States, Have High Rates of Hepatitis C Infection and Limited Testing History.

BACKGROUND: Cases of newly identified hepatitis C virus (HCV) infection increased 3.8-fold between 2010 and 2017 due to increasing injection drug use. Furthermore, multiple HIV outbreaks have been attributed to injection drug use. This retrospective cohort study assessed the prevalence of and testing history for HIV and HCV among opioid overdose patients in the emergency department. METHODS: Each encounter including an opioid overdose at three emergency departments between January 2021 and May 2022 was reviewed. Emergency department note, most recent primary care note, and laboratory results from January 2000 to May 2022 were reviewed for the history of HIV and HCV testing. Fisher's exact test was used to identify associations of HIV and HCV status with age or gender. RESULTS: There were 134 encounters for 120 patients. A total of 72 were male and 48 were female. A total of 48 had a history of HCV testing. A total of 54 had a history of HIV testing. A total of 20 tested positive for HCV antibodies. One tested positive for HIV. Eight had detectable HCV viral loads, six had undetectable HCV viral loads, and six had no quantitative testing. One had a detectable HIV viral load. A total of 16.7% of both males and females had a history of a positive HCV test. Females were more likely to have ever received an HCV test compared to males (p=0.013, odds ratio (OR)=.68 (confidence interval (CI): 1.293-5.836)). Patients aged 55-64 were more likely to test positive than any other age group (p=0.018, OR=3.889 (CI: 1.391-11.81)), and were the least likely to be untested (p=0.037, OR=0.1905 (CI: 0.03914-0.9334)). CONCLUSION: There is a substantial burden of HCV among opioid overdose patients in central Missouri, United States, emergency departments, particularly among male patients and those aged 55-64. Universal HCV screening for individuals being observed following an overdose could detect many undiagnosed HCV infections.

Evaluating the Quality and Impact of TikTok Videos on Autologous Breast Reconstruction with Deep Inferior Epigastric Perforator Artery Flaps.

Background: With the rising influence of social media on healthcare perceptions, this study investigates TikTok's role in educating the public about autologous breast reconstruction, specifically focusing on deep inferior epigastric perforator flaps. Methods: We conducted a systematic analysis of 152 TikTok videos related to deep inferior epigastric perforator flap procedures, evaluating the accuracy of the content, viewer engagement metrics, and the influence of content creator characteristics on viewer interactions. Results: Our analysis identified a wide variance in the quality of information, with many videos lacking in-depth educational content, thereby posing a risk of misinformation. Despite the presence of high-quality educational videos, there was a discrepancy between the educational value provided and viewer engagement levels. Thematic analysis highlighted common concerns among patients, providing insights for healthcare professionals to better tailor their social media content. Conclusions: The study underscores the significant impact of platforms like TikTok on patient education and emphasizes the need for healthcare professionals to guide the narrative on social media and ensure the dissemination of accurate and helpful information, ultimately aiding patients in making informed decisions about their healthcare.

Amidino-rocaglates (ADRs), a class of synthetic rocaglates, are potent inhibitors of SARS-CoV-2 replication through inhibition of viral protein synthesis.

Coronaviruses are highly transmissible respiratory viruses that cause symptoms ranging from mild congestion to severe respiratory distress. The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the need for new antivirals with broad-acting mechanisms to combat increasing emergence of new variants. Currently, there are only a few antivirals approved for treatment of SARS-CoV-2. Previously, the rocaglate natural product silvestrol and synthetic rocaglates such as CR-1-31b were shown to have antiviral effects by inhibiting eukaryotic translation initiation factor 4A1 (eIF4A) function and virus protein synthesis. In this study, we evaluated amidino-rocaglates (ADRs), a class of synthetic rocaglates with the most potent eIF4A-inhibitory activity to-date, for inhibition of SARS-CoV-2 infection. This class of compounds showed low nanomolar potency against multiple SARS-CoV-2 variants and in multiple cell types, including human lung-derived cells, with strong inhibition of virus over host protein synthesis and low cytotoxicity. The most potent ADRs were also shown to be active against two highly pathogenic and distantly related coronaviruses, SARS-CoV and MERS-CoV. Mechanistically, cells with mutations of eIF4A1, which are known to reduce rocaglate interaction displayed reduced ADR-associated loss of cellular function, consistent with targeting of protein synthesis. Overall, ADRs and derivatives may offer new potential treatments for SARS-CoV-2 with the goal of developing a broad-acting anti-coronavirus agent.

Acroamine A, a 2-Amino Adenine Alkaloid from the Marine Soft Coral Acrozoanthus australiae and Its Semisynthetic Derivatives That Inhibit cAMP-Dependent Protein Kinase A Catalytic Subunit Alpha.

A high throughput screen performed to identify catalytic inhibitors of the oncogenic fusion form of cAMP-dependent protein kinase A catalytic subunit alpha (J-PKAcα) found an individual fraction from an organic extract of the marine soft coral Acrozoanthus australiae as active. Bioassay-guided isolation led to the identification of a 2-amino adenine alkaloid acroamine A (1), the first secondary metabolite discovered from this genus and previously reported as a synthetic product. As a naturally occurring protein kinase inhibitor, to unambiguously assign its chemical structure using modern spectroscopic and spectrometric techniques, five N-methylated derivatives acroamines A1-A5 (2-6) were semisynthesized. Three additional brominated congeners A6-A8 (7-9) were also semisynthesized to investigate the structure-activity relationship of the nine compounds as J-PKAcα inhibitors. Compounds 1-9 were tested for J-PKAcα and wild-type PKA inhibitory activities, which were observed exclusively in acroamine A (1) and its brominated analogs (7-9) achieving moderate potency (IC50 2-50 µM) while none of the N-methylated analogs exhibited kinase inhibition.

A Caged Neutral 17-Valence-Electron Iron(I) Radical [Fe(CO)2(Cl)(P((CH2)10)3P)]•: Synthetic, Structural, Spectroscopic, Redox, and Computational Studies.

UV irradiation of yellow CH2Cl2 solutions of trans-Fe(CO)3(P((CH2)10)3P) (2a) and PMe3 (10 equiv) gives, in addition to the previously reported dibridgehead diphosphine P((CH2)10)3P (46%), a green paramagnetic complex that crystallography shows to be the trigonal-bipyramidal iron(I) radical trans-[Fe(CO)2(Cl)(P((CH2)10)3P)]• (1a•; 31% after workup). This is a rare example of an isolable species of the formula [Fe(CO)4-n(L)n(X)]• (n = 0-3, L = two-electron-donor ligand; X = one-electron-donor ligand). Analogous precursors with longer P(CH2)nP segments (n = 12, 14, 16, 18) give only the demetalated diphosphines, and a rationale is proposed. The magnetic susceptibility of 1a•, assayed by Evans' method and SQUID measurements, indicates a spin (S) of 1/2. Cyclic voltammetry shows that 1a• undergoes a partially reversible one-electron oxidation, but no facile reduction. The UV-visible, EPR, and 57Fe Mössbauer spectra are analyzed in detail. Complex 2a is similarly studied, and, despite the extra valence electron, exhibits a comparable oxidation potential (ΔE1/2 ≤ 0.04 V). The crystal structure shows a cage conformation, solvation level, disorder motif, and unit cell parameters essentially identical to those of 1a•. DFT calculations provide much insight regarding the structural, redox, and spectroscopic properties.

Investigating the In Vivo Biodistribution of Extracellular Vesicles Isolated from Various Human Cell Sources Using Positron Emission Tomography.

Positron emission tomography (PET) is a powerful tool for investigating the in vivo behavior of drug delivery systems. We aimed to assess the biodistribution of extracellular vesicles (EVs), nanosized vesicles secreted by cells isolated from various human cell sources using PET. EVs were isolated from mesenchymal stromal cells (MSCs) (MSC EVs), human macrophages (Mϕ EVs), and a melanoma cell line (A375 EVs) by centrifugation and were conjugated with deferoxamine for radiolabeling with Zr-89. PET using conjugated and radiolabeled EVs evaluated their in vivo biodistribution and tissue tropisms. Our study also investigated differences in mouse models, utilizing immunocompetent and immunocompromised mice and an A375 xenograft tumor model. Lastly, we investigated the impact of different labeling techniques on the observed EV biodistribution, including covalent surface modification and membrane incorporation. PET showed that all tested EVs exhibited extended in vivo circulation and generally low uptake in the liver, spleen, and lungs. However, Mϕ EVs showed high liver uptake, potentially attributable to the intrinsic tissue tropism of these EVs from the surface protein composition. MSC EV biodistribution differed between immunocompetent and immunodeficient mice, with increased spleen uptake observed in the latter. PET using A375 xenografts demonstrated efficient tumor uptake of EVs, but no preferential tissue-specific tropism of A375 EVs was found. Biodistribution differences between labeling techniques showed that surface-conjugated EVs had preferential blood circulation and low liver, spleen, and lung uptake compared to membrane integration. This study demonstrates the potential of EVs as effective drug carriers for various diseases, highlights the importance of selecting appropriate cell sources for EV-based drug delivery, and suggests that EV tropism can be harnessed to optimize therapeutic efficacy. Our findings indicate that the cellular source of EVs, labeling technique, and animal model can influence the observed biodistribution.

Transcranial Endovascular Embolization of Dural Arteriovenous Fistula: A Case Report and Literature Review.

The optimal endovascular management of high-grade dural arterial-venous fistulae (dAVF) can be technically challenging in cases where the involved venous sinus segment is inaccessible through the traditional percutaneous approach. In this report, we describe our experience with the transcranial endovascular approach for the treatment of a high-grade dAVF. We also provide a literature review of other reports of transcranial endovascular dAVF embolization. We propose that transcranial endovascular embolization of high-grade dAVF appears to be safe and effective in cases where the fistula is inaccessible to percutaneous routes alone.