Osteogenic Potential and Long-Term Enzymatic Biodegradation of PHB-based Scaffolds with Composite Magnetic Nanofillers in a Magnetic Field.

Millions of people worldwide suffer from musculoskeletal damage, thus using the largest proportion of rehabilitation services. The limited self-regenerative capacity of bone and cartilage tissues necessitates the development of functional biomaterials. Magnetoactive materials are a promising solution due to clinical safety and deep tissue penetration of magnetic fields (MFs) without attenuation and tissue heating. Herein, electrospun microfibrous scaffolds were developed based on piezoelectric poly(3-hydroxybutyrate) (PHB) and composite magnetic nanofillers [magnetite with graphene oxide (GO) or reduced GO]. The scaffolds' morphology, structure, mechanical properties, surface potential, and piezoelectric response were systematically investigated. Furthermore, a complex mechanism of enzymatic biodegradation of these scaffolds is proposed that involves (i) a release of polymer crystallites, (ii) crystallization of the amorphous phase, and (iii) dissolution of the amorphous phase. Incorporation of Fe3O4, Fe3O4-GO, or Fe3O4-rGO accelerated the biodegradation of PHB scaffolds owing to pores on the surface of composite fibers and the enlarged content of polymer amorphous phase in the composite scaffolds. Six-month biodegradation caused a reduction in surface potential (1.5-fold) and in a vertical piezoresponse (3.5-fold) of the Fe3O4-GO scaffold because of a decrease in the PHB ß-phase content. In vitro assays in the absence of an MF showed a significantly more pronounced mesenchymal stem cell proliferation on composite magnetic scaffolds compared to the neat scaffold, whereas in an MF (68 mT, 0.67 Hz), cell proliferation was not statistically significantly different when all the studied scaffolds were compared. The PHB/Fe3O4-GO scaffold was implanted into femur bone defects in rats, resulting in successful bone repair after nonperiodic magnetic stimulation (200 mT, 0.04 Hz) owing to a synergetic influence of increased surface roughness, the presence of hydrophilic groups near the surface, and magnetoelectric and magnetomechanical effects of the material.

Mesenchymal stem cells in wound healing: A bibliometric analysis as a powerful research tool.

Bibliographic analysis is still very rarely used in experimental basic study papers. The comprehensive bibliometric analysis of scientific literature on research progress and challenges in stem cell therapy for diabetic chronic wounds, which was conducted in the work of Shi et al can be a case study and a source of valuable information for writing reviews and experimental papers in this field. Basic experimental studies on a role of mesenchymal stem cells (MSCs) in wound healing that are published in 2023-2024, such as Zhang et al in 2023, Hu et al in 2023, Wang et al in 2023 are certainly also subjects for applying this powerful tool to analyze current research, challenges and perspectives in this field. This is due to the fact that these studies have addressed a great variety of aspects of the application of MSCs for the treatment of chronic wounds, such as using both the cells themselves and their various products: Sponges, hydrogels, exosomes, and genetic constructions. Such a wide variety of directions in the field of study and biomedical application of MSCs requires a deep understanding of the current state of research in this area, which can be provided by bibliometric analysis. Thus, the use of such elements of bibliographic analysis as publication count by year and analysis of top-10 keywords calculated independently or cited from bibliometric analysis studies can be safely recommended for every basic study manuscripts, primarily for the "Introduction" section, and review.

Enhanced Nitric Oxide Delivery Through Self-Assembling Nanoparticles for Eradicating Gram-Negative Bacteria.

In the current battle against antibiotic resistance, the resilience of Gram-negative bacteria against traditional antibiotics is due not only to their protective outer membranes but also to mechanisms like efflux pumps and enzymatic degradation of drugs, underscores the urgent need for innovative antimicrobial tactics. Herein, this study presents an innovative method involving the synthesis of three furoxan derivatives engineered to self-assemble into nitric oxide (NO) donor nanoparticles (FuNPs). These FuNPs, notably supplied together with polymyxin B (PMB), achieve markedly enhanced bactericidal efficacy against a wide spectrum of bacterial phenotypes at considerably lower NO concentrations (0.1-2.8 µg mL-1), which is at least ten times lower than the reported data for NO donors (≥200 µg mL-1). The bactericidal mechanism is elucidated using confocal, scanning, and transmission electron microscopy techniques. Neutron reflectometry confirms that FuNPs initiate membrane disruption by specifically engaging with the polysaccharides on bacterial surfaces, causing structural perturbations. Subsequently, PMB binds to lipid A on the outer membrane, enhancing permeability and resulting in a synergistic bactericidal action with FuNPs. This pioneering strategy underscores the utility of self-assembly in NO delivery as a groundbreaking paradigm to circumvent traditional antibiotic resistance barriers, marking a significant leap forward in the development of next-generation antimicrobial agents.

Cognitive behavioral self-help interventions for individuals experiencing psychosis: a systematic review.

Little is known about the effectiveness of cognitive behavioral therapy (CBT) specific self-help for psychosis, given that CBT is a highly recommended treatment for psychosis. Thus, research has grown regarding CBT-specific self-help for psychosis, warranting an overall review of the literature. A systematic literature review was conducted, following a published protocol which can be found at: https://www.crd.york.ac.uk/prospero/export_record_pdf.php. A search was conducted across Scopus, PubMed, PsycInfo, and Web of Science to identify relevant literature, exploring CBT-based self-help interventions for individuals experiencing psychosis. The PICO search strategy tool was used to generate search terms. A narrative synthesis was conducted of all papers, and papers were appraised for quality. Ten studies were included in the review. Seven papers found credible evidence to support the effectiveness of CBT-based self-help in reducing features of psychosis. Across the studies, common secondary outcomes included depression, overall psychological well-being, and daily functioning, all of which were also found to significantly improve following self-help intervention, as well as evidence to support its secondary benefit for depression, anxiety, overall well-being, and functioning. Due to methodological shortcomings, long-term outcomes are unclear.

Measuring clinically relevant change in apathy symptoms in ADMET and ADMET 2.

OBJECTIVES: Among participants with Alzheimer's disease (AD) we estimated the minimal clinically important difference (MCID) in apathy symptom severity on three scales. DESIGN: Retrospective anchor- and distribution-based analyses of change in apathy symptom scores. SETTING: Apathy in Dementia Methylphenidate Trial (ADMET) and ADMET 2 randomized controlled trials conducted at three and ten clinics specialized in dementia care in United States and Canada, respectively. PARTICIPANTS: Two hundred and sixty participants (60 ADMET, 200 ADMET 2) with clinically significant apathy in Alzheimer's disease. MEASUREMENTS: The Clinical Global Impression of Change in Apathy scale was used as the anchor measure and the MCID on the Neuropsychiatric Inventory - Apathy (NPI-A), Dementia Apathy Interview and Rating (DAIR), and Apathy Evaluation Scale-Informant (AES-I) were estimated with linear mixed models across all study visits. The estimated thresholds were evaluated with performance metrics. RESULTS: Among the MCID was a decrease of four points (95% CI: -4.0 to -4.8) on the NPI-A, 0.56 points (95% CI: -0.47 to -0.65) on the DAIR, and three points on the AES-I (95% CI: -0.9 to -5.4). Distribution-based analyses were largely consistent with the anchor-based analyses. The MCID across the three measures showed ∼60% accuracy. Sensitivity analyses found that MMSE scores and apathy severity at baseline influenced the estimated MCID. CONCLUSIONS: MCIDs for apathy on three scales will help evaluate treatment efficacy at the individual level. However, the modest correspondence between MCID and clinical impression of change suggests the need to consider other scales.

Early- and life-long intake of dietary advanced glycation end-products (dAGEs) leads to transient tissue accumulation, increased gut sensitivity to inflammation, and slight changes in gut microbial diversity, without causing overt disease.

Dietary advanced glycation end-products (dAGEs) accumulate in organs and are thought to initiate chronic low-grade inflammation (CLGI), induce glycoxidative stress, drive immunosenescence, and influence gut microbiota. Part of the toxicological interest in glycation products such as dietary carboxymethyl-lysine (dCML) relies on their interaction with receptor for advanced glycation end-products (RAGE). It remains uncertain whether early or lifelong exposure to dAGEs contributes physiological changes and whether such effects are reversible or permanent. Our objective was to examine the physiological changes in Wild-Type (WT) and RAGE KO mice that were fed either a standard diet (STD - 20.8 ± 5.1 µg dCML/g) or a diet enriched with dCML (255.2 ± 44.5 µg dCML/g) from the perinatal period for up to 70 weeks. Additionally, an early age (6 weeks) diet switch (dCML→STD) was explored to determine whether potential harmful effects of dCML could be reversed. Previous dCML accumulation patterns described by our group were confirmed here, with significant RAGE-independent accumulation of dCML in kidneys, ileum and colon over the 70-week dietary intervention (respectively 3-fold, 17-fold and 20-fold increases compared with controls). Diet switching returned tissue dCML concentrations to their baseline levels. The dCML-enriched diet had no significative effect on endogenous glycation, inflammation, oxidative stress or senescence parameters. The relative expression of TNFα, VCAM1, IL6, and P16 genes were all upregulated (∼2-fold) in an age-dependent manner, most notably in the kidneys of WT animals. RAGE knockout seemed protective in this regard, diminishing age-related renal expression of TNFα. Significant increases in TNFα expression were detectable in the intestinal tract of the Switch group (∼2-fold), suggesting a higher sensitivity to inflammation perhaps related to the timing of the diet change. Minor fluctuations were observed at family level within the caecal microbiota, including Eggerthellaceae, Anaerovoracaceae and Marinifilaceae communities, indicating slight changes in composition. Despite chronic dCML consumption resulting in higher free CML levels in tissues, there were no substantial increases in parameters related to inflammageing. Age was a more important factor in inflammation status, notably in the kidneys, while the early-life dietary switch may have influenced intestinal susceptibility to inflammation. This study affirms the therapeutic potential of RAGE modulation and corroborates evidence for the disruptive effect of dietary changes occurring too early in life. Future research should prioritize the potential influence of dAGEs on disease aetiology and development, notably any exacerbating effects they may have upon existing health conditions.

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.

Electronic Force Density Fields: Insights into Partial Bonds, Transition States, and Chemical Structure Evolution.

This paper presents the quantum-topological binding approach, in which the electrostatic and total static force density fields, Fes(r) and F(r), together with the electron density gradient field ∇ρ(r), are simultaneously analyzed to elucidate the chemical structure of transition states and the nature of interatomic interactions for semibroken semiformed partial chemical bonds. The approach attributes the discrepancies between the force fields F(r) and Fes(r) to the nonclassical electron-electron interaction effects. The internuclear gap between the zero-flux boundaries of Fes(r) and ∇ρ(r) indicates the interatomic charge transfer phenomenon (ICT) that occurs upon the formation of a system from free atoms. Concomitantly, the mismatch of the zero-flux surfaces defined in -F(r) and ∇ρ(r) can be interpreted as a phenomenon of the electron-transfer-induced quantum chemical response (QCR), which originates from the electron exchange correlation. Our study permits the assertion of parallels between partial bonds and noncovalent interactions, as both typically exhibit incomplete QCRs, indicating the partial electron sharing of the transferred density. The changes in atomic and pseudoatomic charges are employed to describe the evolution of the chemical structure upon the substitution reaction. It is observed that the acquired difference in the actual atomic electronegativity causes polarization upon the heterolytic breaking of virtually nonpolar bonds. It is further proposed that the proximity of closely related stationary states along the reaction path on a potential energy hypersurface implies their similarity in the manifestation of the ICT and sympathetic QCR. Furthermore, the involvement of an electron pair in a partial bond facilitates its delocalization through the attraction by the static forces F(r) and Fes(r) to a neighboring nucleus and through the smearing by the Pauli kinetic force FP(r).

Scaling up ocean conservation through recognition of key biodiversity areas in the Southern Ocean from multispecies tracking data.

Biodiversity is critical for maintaining ecosystem function but is threatened by increasing anthropogenic pressures. In the Southern Ocean, a highly biologically productive region containing many endemic species, proactive management is urgently needed to mitigate increasing pressures from fishing, climate change, and tourism. Site-based conservation is one important tool for managing the negative impacts of human activities on ecosystems. The Key Biodiversity Area (KBA) Standard is a standardized framework used to define sites vital for the persistence of global biodiversity based on criteria and quantitative thresholds. We used tracking data from 14 species of Antarctic and subantarctic seabirds and pinnipeds from the publicly available Retrospective Analysis of Antarctic Tracking Data (RAATD) data set to define KBAs for a diverse suite of marine predators. We used track2kba, an R package that supports identification of KBAs from telemetry data through identification of highly used habitat areas and estimates of local abundance within sites. We compared abundance estimates at each site with thresholds for KBA criteria A1, B1, and D1 (related to globally threatened species, individual geographically restricted species, and demographic aggregations, respectively). We identified 30 potential KBAs for 13 species distributed throughout the Southern Ocean that were vital for each individual species, population, and life-history stage for which they were determined. These areas were identified as highly used by these populations based on observational data and complement the ongoing habitat modeling and bioregionalization work that has been used to prioritize conservation areas in this region. Although further work is needed to identify potential KBAs based on additional current and future data sets, we highlight the benefits of utilizing KBAs as part of a holistic approach to marine conservation, given their significant value as a global conservation tool.

Ampliación de la conservación oceánica por medio del reconocimiento de áreas importantes de biodiversidad en el Océano Antártico a partir de datos de rastreo de varias especies Resumen La biodiversidad es fundamental para mantener la función de los ecosistemas, pero está amenazada por las crecientes presiones antropogénicas. En el Océano Antártico, una región con mucha producción biológica que contiene numerosas especies endémicas, se necesita urgentemente una gestión proactiva para mitigar las crecientes presiones de la pesca, el cambio climático y el turismo. La conservación basada en el sitio es una herramienta importante para gestionar los efectos negativos de las actividades humanas en los ecosistemas. El Estándar de Áreas Clave para la Biodiversidad (ACB) es un marco estandarizado que se utiliza para definir lugares vitales para la persistencia de la biodiversidad mundial con base en criterios y umbrales cuantitativos. Usamos datos del seguimiento de 14 especies de aves marinas y pinnípedos antárticos y sub­antárticos del conjunto de datos públicos Retrospective Analysis of Antarctic Tracking Data (RAATD) para definir las ACB de un conjunto diverso de depredadores marinos. Utilizamos track2kba, un paquete de R que permite la identificación de ACB a partir de datos telemétricos mediante la identificación de áreas de hábitat altamente utilizadas y estimaciones de abundancia local dentro de los sitios. Comparamos las estimaciones de abundancia en cada lugar con los umbrales de los criterios A1, B1 y D1 de las ACB (relacionados con especies amenazadas a nivel mundial, especies individuales restringidas geográficamente y agregaciones demográficas, respectivamente). Identificamos 30 ACB potenciales para 13 especies distribuidas por todo el Océano Antártico que eran vitales para cada especie individual, población y etapa del ciclo biológico para las que se determinaron. Estas áreas fueron identificadas como muy utilizadas por estas poblaciones con base a datos observacionales y complementan el trabajo en curso de modelos del hábitat y biorregionalización que se ha utilizado para priorizar las áreas de conservación en esta región. Aunque es necesario seguir trabajando para identificar posibles ACB basadas en conjuntos de datos adicionales actuales y futuros, destacamos los beneficios de utilizar las ACB como parte de un enfoque holístico de la conservación marina, dado su importante valor como herramienta de conservación global.

Brexpiprazole for Agitation Associated With Dementia Due to Alzheimer's Disease.

Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by progressive cognitive and functional decline. Nearly all patients with AD develop neuropsychiatric symptoms (NPSs). Agitation is one of the most distressing and challenging NPS. Brexpiprazole is an oral antipsychotic and is the first approved pharmacologic agent in the United States for the treatment of agitation associated with dementia due to AD. Its effect is thought to be from its partial serotonin 5-HT1A and dopamine D2 receptor agonist activity and serotonin 5-HT2A receptor antagonism. Brexpiprazole is a maintenance medication, and it should not be used "as needed" or as a "PRN" treatment for breakthrough agitation. Brexpiprazole is a major substrate of CYP2D6 and CYP3A4. Dose adjustments may be required for drug interactions or impaired renal or hepatic function. Clinical trials found brexpiprazole 2 to 3 mg/d demonstrated significant improvements in agitation, with brexpiprazole showing an approximate 5-point greater reduction on change in the Cohen-Mansfield Agitation Inventory total score at week 12 from baseline compared with placebo. Brexpiprazole is generally well tolerated and safe, and common adverse reactions when used for this indication include dizziness, headaches, insomnia, nasopharyngitis, somnolence, and urinary tract infections. Like other antipsychotics used for agitation in AD, brexpiprazole is associated with higher mortality rates compared with placebo. In a long-term care setting, there are several considerations for its use. Benefits include an oral agent that is well tolerated and clinical data showing statistically significant effects on agitation. However, brexpiprazole has not been studied in head-to-head clinical trials against other antipsychotics, and there are differing opinions if the agitation score reductions translate to a clinically meaningful difference. The approval of brexpiprazole signals favorably for upcoming agents for this indication, including escitalopram and dextromethorphan-bupropion. Both escitalopram and dextromethorphan-bupropion are currently undergoing clinical trials.

Synthesis of Technetium Carboxylates: Wheel-Like Octanuclear Clusters (Tc8(µ-O)8(RCOO)16, Where R = CF3, C6H5)─Potential Nanobuilding Units for Tc-MOFs.

Herein, we studied the behavior of TcO4- in trifluoroacetic anhydride (TFAA) under visible light irradiation in situ by UV-vis spectroscopy. One carboxylate of Tc(VII) C2F3O5Tc (1) and two wheel-like carboxylate clusters of Tc(IV) Tc8(µ-O)8(CF3COO)16 (2, 3) and Tc8(µ-O)8(C6H5COO)16 (4) were synthesized and analyzed using pXRD, TGA, UV-vis spectroscopy, and SCXRD techniques. According to SCXRD, it was found that Tc(IV) trifluoroacetate exists in two crystalline modifications. By UV-vis spectroscopy and DFT calculations, it was shown that the primary compound in the reaction system is trifluoroacetate Tc(VII). A technetium trifluoroacetate(VII) and Tc intermediates of unidentified nature both show photosensitivity. The influence of intermolecular noncovalent interactions on the volatility of trifluoroacetate and benzoate Tc(IV) is shown. The main regularities of chemical transformations of technetium in nonaqueous solutions of carboxylates have been revealed. The obtained data on the kinetics of the process suggest that technetium in trifluoroacetic anhydride can simultaneously exist in the form of Tc(VII), Tc(VI), Tc(V), and Tc(IV). Under laser ionization or prolonged heating, the formation of the Tc(II,III)-cluster is observed.

Arginine catabolism is essential to polymyxin dependence in Acinetobacter baumannii.

Polymyxins are often the only effective antibiotics against the "Critical" pathogen Acinetobacter baumannii. Worryingly, highly polymyxin-resistant A. baumannii displaying dependence on polymyxins has emerged in the clinic, leading to diagnosis and treatment failures. Here, we report that arginine metabolism is essential for polymyxin-dependent A. baumannii. Specifically, the arginine degradation pathway was significantly altered in polymyxin-dependent strains compared to wild-type strains, with critical metabolites (e.g., L-arginine and L-glutamate) severely depleted and expression of the astABCDE operon significantly increased. Supplementation of arginine increased bacterial metabolic activity and suppressed polymyxin dependence. Deletion of astA, the first gene in the arginine degradation pathway, decreased phosphatidylglycerol and increased phosphatidylethanolamine levels in the outer membrane, thereby reducing the interaction with polymyxins. This study elucidates the molecular mechanism by which arginine metabolism impacts polymyxin dependence in A. baumannii, underscoring its critical role in improving diagnosis and treatment of life-threatening infections caused by "undetectable" polymyxin-dependent A. baumannii.

Adverse effects of methylphenidate for apathy in patients with Alzheimer's disease (ADMET2 trial).

OBJECTIVES: To examine clinically important adverse events (AEs) associated with methylphenidate (MPH) treatment of apathy in Alzheimer's Disease (AD) versus placebo, including weight loss, vital signs, falls, and insomnia. METHODS: The Apathy in Dementia Methylphenidate Trial 2 (ADMET2) trial was a multicenter randomized, placebo-controlled trial of MPH to treat apathy in individuals with apathy and AD. Participants in ADMET2 had vital signs and weight measured at monthly visits through 6 months. AEs, including insomnia, falls, and cardiovascular events, were reported at every visit by participants and families using a symptom checklist. RESULTS: The study included 98 participants in the MPH group and 101 in the placebo group. Participants in the MPH group experienced greater weight loss on average than the placebo through the 6-month follow-up, with a difference in change between MPH and placebo of 2.8 lb (95% confidence interval, CI: 0.7, 4.9 lb). No treatment group differences in change during the trial were found in systolic and diastolic blood pressure. More participants in the MPH group reported falls during the follow-up, 10 versus 6 in MPH and placebo groups, respectively. No differences in post-baseline insomnia were observed between the treatment groups. No participants reported instances of myocardial infarction, congestive heart failure, arrhythmia, stroke, or cardiomyopathy throughout the study period. CONCLUSIONS: MPH use in AD patients for treating apathy is relatively safe, particularly notable given the many medical comorbidities in this population. There was a statistically significant but modest weight loss associated with MPH use, and clinicians are thus advised to monitor weight during MPH treatment.

Dataset on investigating nucleation and growth kinetics of methane hydrate in aqueous methanol solutions.

This work systematically investigates the effect of methanol (MeOH) in a wide range of concentrations (0, 1, 2.5, 5, 10, 20, 30, 40, and 50 mass%) on methane hydrate nucleation and growth kinetics. Multiple measurements of gas hydrate onset temperatures and pressures for CH4-H2O and CH4-MeOH-H2O systems were performed by ramp cooling experiments (1 K/h) using sapphire rocking cell RCS6 apparatus. The dataset comprises 96 ramp experiments conducted under identical initial conditions for each solution (gas pressure of 8.1 MPa at 295 K). The reported hydrate onset temperatures and pressures range within 248-282 K and 6.2-7.5 MPa, respectively. The methane hydrate onset subcooling was calculated using literature data on the three-phase gas-aqueous solution-gas hydrate equilibrium for the studied systems. The study determined the numerical values of the shape and scale parameters of gamma distributions that describe the empirical dependences of methane hydrate nucleation cumulative probability as a function of hydrate onset subcooling in the aqueous methanol solutions. Gas uptake curves were analyzed to characterize the kinetics of methane hydrate growth under polythermal conditions at different methanol concentrations.

Real-world performance of Uromonitor® in urothelial bladder cancer detection: a multicentric trial.

OBJECTIVES: To compare Uromonitor® (U-Monitor Lda, Porto, Portugal), a multitarget DNA assay that detects mutated proto-oncogenes (telomerase reverse transcriptase [TERT], fibroblast growth factor receptor 3 [FGFR-3], Kirsten rat sarcoma viral oncogene homologue [KRAS]), with urine cytology in the urine-based diagnosis of urothelial carcinoma of the bladder (UCB) within a multicentre real-world setting. PATIENTS AND METHODS: This multicentre, prospective, double-blind study was conducted across four German urological centres from 2019 to 2024. We evaluated the diagnostic performance of Uromonitor compared to urine cytology in a cohort of patients with UCB and in healthy controls within a real-world setting. Sensitivity, specificity, positive-predictive value (PPV), negative-predictive value (NPV), and accuracy of the tests were measured, in addition to multivariate analyses to assess the ability of individual proto-oncogene mutations in detecting UCB. The biometric sample size was designed to achieve a 10% difference in sensitivity. RESULTS: Patients with UCB comprised 63.7% (339/532) of the study group. Uromonitor showed a sensitivity, specificity, PPV, NPV, accuracy, and an area-under-the-curve of 49.3%, 93.3%, 92.8%, 51.1%, 65.2%, and 0.713%, respectively. These metrics did not demonstrate statistical superiority over urine cytology in terms of sensitivity (44.6%; P = 0.316). Moreover, the comparison of additional test parameters, as well as the comparison within various sensitivity analyses, yielded no significant disparity between the two urinary tests. Multivariate logistic regression underscored the significant predictive value of a positive Uromonitor for detecting UCB (odds ratio [OR] 9.03; P < 0.001). Furthermore, mutations in TERT and FGFR-3 were independently associated with high odds of UCB detection (OR 13.30 and 7.04, respectively), while KRAS mutations did not exhibit predictive capability. CONCLUSION: Despite its innovative approach, Uromonitor fell short of confirming the superior results anticipated from previous studies in this real-world setting. The search for an optimal urine-based biomarker for detecting and monitoring UCB remains ongoing. Results from this study highlight the complexity of developing non-invasive diagnostic tools and emphasise the importance of continued research efforts to refine these technologies.

iPSC-derived hindbrain organoids to evaluate escitalopram oxalate treatment responses targeting neuropsychiatric symptoms in Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia, and the gradual deterioration of brain function eventually leads to death. Almost all AD patients suffer from neuropsychiatric symptoms (NPS), the emergence of which correlates with dysfunctional serotonergic systems. Our aim is to generate hindbrain organoids containing serotonergic neurons using human induced Pluripotent Stem Cells (iPSCs). Work presented here is laying the groundwork for the application of hindbrain organoids to evaluate individual differences in disease progression, NPS development, and pharmacological treatment response. Human peripheral blood mononuclear cells (PBMCs) from healthy volunteers (n = 3), an AD patient without NPS (n = 1), and AD patients with NPS (n = 2) were reprogrammed into iPSCs and subsequently differentiated into hindbrain organoids. The presence of serotonergic neurons was confirmed by quantitative reverse transcription PCR, flow cytometry, immunocytochemistry, and detection of released serotonin (5-HT). We successfully reprogrammed PBMCs into 6 iPSC lines, and subsequently generated hindbrain organoids from 6 individuals to study inter-patient variability using a precision medicine approach. To assess patient-specific treatment effects, organoids were treated with different concentrations of escitalopram oxalate, commonly prescribed for NPS. Changes in 5-HT levels before and after treatment with escitalopram were dose-dependent and variable across patients. Organoids from different people responded differently to the application of escitalopram in vitro. We propose that this 3D platform might be effectively used for drug screening purposes to predict patients with NPS most likely to respond to treatment in vivo and to understand the heterogeneity of treatment responses.

HIV and influenza fusion peptide interactions with (dis)ordered lipid bilayers: Understanding mechanisms and implications for antimicrobial and antiviral approaches.

The interactions of viral fusion peptides from influenza (E4K and Ac-E4K) and human immunodeficiency virus (gp41 and Ac-gp41) with planar lipid bilayers and monolayers was investigated herein. A combination of surface-sensitive techniques, including quartz crystal microbalance with dissipation (QCM-D), Langmuir-Blodgett area-pressure isotherms with Micro-Brewster angle microscopy, and neutron reflectometry, was employed. Differences in the interactions of the viral fusion peptides with lipid bilayers featuring ordered and disordered phases, as well as lipid rafts, were revealed. The HIV fusion peptide (gp41) exhibited strong binding to the DOPC/DOPS bilayer, comprising a liquid disordered phase, with neutron reflectometry (NR) showing interaction with the bilayer's headgroup area. Conversely, negligible binding was observed with lipid bilayers in a liquid ordered phase. Notably, the influenza peptide (E4K) demonstrated slower binding kinetics with DOPC/DOPS bilayers and distinct interactions compared to gp41, as observed through QCM-D. This suggests different mechanisms of interaction with the lipid bilayers: one peptide interacts more within the headgroup region, while the other is more involved in transmembrane interactions. These findings hold implications for understanding viral fusion mechanisms and developing antimicrobials and antivirals targeting membrane interactions. The differential binding behaviours of the viral fusion peptides underscore the importance of considering membrane composition and properties in therapeutic strategy design.

Psychological distress, wellbeing and resilience: modelling adolescent mental health profiles during the COVID-19 pandemic.

There has been concern about adolescent mental health during the pandemic. The current study examined adolescent mental health during the initial phase of the COVID-19 pandemic in the UK. Using indicator of psychological distress, wellbeing and resilience, latent profile analysis was used to identify homogeneous mental health groups among young people aged 13-24 (N = 1971). Multinomial logistic regression was then used to examine which sociodemographic and psychosocial variables predicted latent class membership. Four classes were found. The largest class (Class 1, 37.2%) was characterised by moderate symptomology and moderate wellbeing. Class 2 (34.2%) was characterised by low symptomology and high wellbeing, while Class 3 (25.4%) was characterised by moderate symptomology and high wellbeing. Finally, Class 4 was the smallest (3.2%) and was characterised by high symptomology and low wellbeing. Compared to the low symptomology, high wellbeing class, all other classes were associated with less social engagement with friends, poorer family functioning, greater somatic symptoms, and a less positive model of self. A number of unique associations between the classes and predictor variables were identified. Although around two-thirds of adolescents reported moderate-to-high symptomology, most of these individuals also reported concurrent moderate-to-high levels of wellbeing, reflecting resilience. Furthermore, these findings demonstrate how a more comprehensive picture of mental health can be gained through adopting a dual-continua conceptualisation of mental health that incorporates both pathology and well-being. In this way, at-risk youth can be identified and interventions and resources targeted appropriately.

Review of valiltramiprosate (ALZ-801) for the treatment of Alzheimer's disease: a novel small molecule with disease modifying potential.

INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive cognitive deterioration, functional impairments, and neuropsychiatric symptoms. Valiltramiprosate is a tramiprosate prodrug being investigated as a novel treatment for AD. AREAS COVERED: The online databases PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched using the terms 'ALZ-801' or 'valiltramiprosate.' Alzheon press releases were reviewed for emerging clinical information. Valiltramiprosate is an oral, well-tolerated synthetic valine-conjugate prodrug of tramiprosate. Valiltramiprosate's active metabolite include tramiprosate and 3-sulfopropanoic acid. Proposed mechanism of action is multiligand binding to Aß42 which stabilizes amyloid monomers to prevent peptide aggregation and oligomerization. Pharmacokinetic studies show 52% oral bioavailability, rapid absorption, approximately 40% brain-drug exposure, and near complete renal clearance. Compared to tramiprosate, valiltramiprosate extends plasma tramiprosate half-life and improves interindividual pharmacokinetic variability. Interim analyses from valiltramiprosate's phase II biomarker trial show: (1) significant reductions in plasma p-tau181 and related AD fluid biomarkers; (2) brain structure preservation and reduced hippocampal atrophy by MRI; and (3) improvements on cognitive assessments at multiple timepoints. Its phase III clinical trial in ApoE ε4 homozygotes is near completion. EXPERT OPINION: Valiltramiprosate's clinical trial data show early indications of efficacy with potential disease modifying effect in AD.

Advances in sample environments for neutron scattering for colloid and interface science.

This review describes recent advances in sample environments across the full complement of applicable neutron scattering techniques to colloid and interface science. Temperature, pressure, flow, tensile testing, ultrasound, chemical reactions, IR/visible/UV light, confinement, humidity and electric and magnetic field application, as well as tandem X-ray methods, are all addressed. Consideration for material choices in sample environments and data acquisition methods are also covered as well as discussion of current and potential future use of machine learning and artificial intelligence.