Peer-led intervention for individuals with major depression: study protocol for a randomized controlled trial (SUPEERMood).

BACKGROUND: Major Depressive Disorder (MDD) is one of the most disabling mental health problems worldwide. The Recovery Model emphasizes peer support to empower individuals with MDD, improve self-management, and patients' quality of life. Despite the demonstrated efficacy of peer-led interventions, further research is needed due to methodological limitations and variability in interventions across studies. Therefore, the objective of this trial is to evaluate the effectiveness of an adjuvant peer-led intervention for the reduction of depressive symptoms in individuals diagnosed with MDD attended in primary care mental health units. METHODS: A controlled, parallel, randomized clinical trial will be conducted. The intervention group (n = 35) will receive 6 weeks of peer-led sessions based on a peer support program drive whilst supervised by nurses, while the control group (n = 35) will use a mobile Health (mHealth) application for emotional wellness based on CBT for 6 weeks. Measurements will be collected at baseline, at 6 weeks, at 6 and 12 months after the intervention to evaluate post-intervention effects. The primary outcome is the reduction of depressive symptoms through the Beck Depression Inventory (BDI-II) after the intervention. Secondary outcomes will involve measures such as adherence to psychiatric treatment, quality of life, adherence to mediterranean diet, alcohol consumption and physical activity. DISCUSSION: We hypothesize that this peer-led intervention, in contrast to the mHealth, will show improvement in BDI-II score reduction of 6 points after six weeks, 6 and 12 months. Standardized peer-led programs can benefit patients and professionals in terms of efficacy and feasibility of clinical treatment of depression, healthy habits, self-care and quality of life. In addition, they can provide recovery and relapse reduction, improved psychosocial support, minimization of intensive care use, and support for patient autonomy through self-management. TRIAL REGISTRATION: The trial protocol is prospectively registered with ClinicalTrials.gov under protocol registration number NCT06398561. Date of registration: May 01, 2024. Recruitment is ongoing.

An experimental, computational, and uncertainty analysis study of the rates of iodoalkane trapping by DABCO in solution phase organic media.

NMR spectroscopy was used to measure the rates of the first and second substitution reactions between iodoalkane (R = Me, 1-butyl) and DABCO in methanol, acetonitrile and DMSO. Most of the reactions were recorded at three different temperatures, which permitted calculation of the activation parameters from Eyring and Arrhenius plots. Additionally, the reaction rate and heat of reaction for 1-iodobutane + DABCO in acetonitrile and DMSO were also measured using calorimetry. To help interpret experimental results, ab initio calculations were performed on the reactant, product, and transition state entities to understand structures, reaction enthalpies and activation parameters. Markov chain Monte Carlo statistical sampling was used to determine a distribution of kinetic rates with respect to the uncertainties in measured concentrations and correlations between parameters imposed by a kinetics model. The reactions with 1-iodobutane are found to be slower in all cases compared to reactions under similar conditions for iodomethane. This is due to steric crowding around the reaction centre for the larger butyl group compared to methyl which results in a larger activation energy for the reaction.

Elucidating Drought-Tolerance Mechanisms in Plant Roots through 1H NMR Metabolomics in Parallel with MALDI-MS, and NanoSIMS Imaging Techniques.

As direct mediators between plants and soil, roots play an important role in metabolic responses to environmental stresses such as drought, yet these responses are vastly uncharacterized on a plant-specific level, especially for co-occurring species. Here, we aim to examine the effects of drought on root metabolic profiles and carbon allocation pathways of three tropical rainforest species by combining cutting-edge metabolomic and imaging technologies in an in situ position-specific 13C-pyruvate root-labeling experiment. Further, washed (rhizosphere-depleted) and unwashed roots were examined to test the impact of microbial presence on root metabolic pathways. Drought had a species-specific impact on the metabolic profiles and spatial distribution in Piper sp. and Hibiscus rosa sinensis roots, signifying different defense mechanisms; Piper sp. enhanced root structural defense via recalcitrant compounds including lignin, while H. rosa sinensis enhanced biochemical defense via secretion of antioxidants and fatty acids. In contrast, Clitoria fairchildiana, a legume tree, was not influenced as much by drought but rather by rhizosphere presence where carbohydrate storage was enhanced, indicating a close association with symbiotic microbes. This study demonstrates how multiple techniques can be combined to identify how plants cope with drought through different drought-tolerance strategies and the consequences of such changes on below-ground organic matter composition.

Decrease of core 2 O-glycans on synovial lubricin in osteoarthritis reduces galectin-3 mediated crosslinking.

The synovial fluid glycoprotein lubricin (also known as proteoglycan 4) is a mucin-type O-linked glycosylated biological lubricant implicated to be involved in osteoarthritis (OA) development. Lubricin's ability to reduce friction is related to its glycosylation consisting of sialylated and unsialylated Tn-antigens and core 1 and core 2 structures. The glycans on lubricin have also been suggested to be involved in crosslinking and stabilization of the lubricating superficial layer of cartilage by mediating interaction between lubricin and galectin-3. However, with the spectrum of glycans being found on lubricin, the glycan candidates involved in this interaction were unknown. Here, we confirm that the core 2 O-linked glycans mediate this lubricin-galectin-3 interaction, shown by surface plasmon resonance data indicating that recombinant lubricin (rhPRG4) devoid of core 2 structures did not bind to recombinant galectin-3. Conversely, transfection of Chinese hamster ovary cells with the core 2 GlcNAc transferase acting on a mucin-type O-glycoprotein displayed increased galectin-3 binding. Both the level of galectin-3 and the galectin-3 interactions with synovial lubricin were found to be decreased in late-stage OA patients, coinciding with an increase in unsialylated core 1 O-glycans (T-antigens) and Tn-antigens. These data suggest a defect in crosslinking of surface-active molecules in OA and provide novel insights into OA molecular pathology.

O-glycosylation on cerebrospinal fluid and plasma apolipoprotein E differs in the lipid-binding domain.

The O-glycoprotein apolipoprotein E (APOE), the strongest genetic risk factor for Alzheimer's disease, associates with lipoproteins. Cerebrospinal fluid (CSF) APOE binds only high-density lipoproteins (HDLs), while plasma APOE attaches to lipoproteins of diverse sizes with binding fine-tuned by the C-terminal loop. To better understand the O-glycosylation on this critical molecule and differences across tissues, we analyzed the O-glycosylation on APOE isolated from the plasma and CSF of aged individuals. Detailed LC-MS/MS analyses allowed the identification of the glycosite and the attached glycan and site occupancy for all detectable glycosites on APOE and further three-dimensional modeling of physiological glycoforms of APOE. APOE is O-glycosylated at several sites: Thr8, Thr18, Thr194, Ser197, Thr289, Ser290 and Ser296. Plasma APOE held more abundant (20.5%) N-terminal (Thr8) sialylated core 1 (Neu5Acα2-3Galß1-3GalNAcα1-) glycosylation compared to CSF APOE (0.1%). APOE was hinge domain glycosylated (Thr194 and Ser197) in both CSF (27.3%) and plasma (10.3%). CSF APOE held almost 10-fold more abundant C-terminal (Thr289, Ser290 and Ser296) glycosylation (36.8% of CSF peptide283-299 was glycosylated, 3.8% of plasma peptide283-299), with sialylated and disialylated (Neu5Acα2-3Galß1-3(Neu5Acα2-6) GalNAcα1-) core 1 structures. Modeling suggested that C-terminal glycosylation, particularly the branched disialylated structure, could interact across domains including the receptor-binding domain. These data, although limited by sample size, suggest that there are tissue-specific APOE glycoforms. Sialylated glycans, previously shown to improve HDL binding, are more abundant on the lipid-binding domain of CSF APOE and reduced in plasma APOE. This indicates that APOE glycosylation may be implicated in lipoprotein-binding flexibility.

APOE in the normal brain.

The APOE4 protein affects the primary neuropathological markers of Alzheimer's disease (AD): amyloid plaques, neurofibrillary tangles, and gliosis. These interactions have been investigated to understand the strong effect of APOE genotype on risk of AD. However, APOE genotype has strong effects on processes in normal brains, in the absence of the hallmarks of AD. We propose that CNS APOE is involved in processes in the normal brains that in later years apply specifically to processes of AD pathogenesis. We review the differences of the APOE protein found in the CNS compared to the plasma, including post-translational modifications (glycosylation, lipidation, multimer formation), focusing on ways that the common APOE isoforms differ from each other. We also review structural and functional studies of young human brains and control APOE knock-in mouse brains. These approaches demonstrate the effects of APOE genotype on microscopic neuron structure, gross brain structure, and behavior, primarily related to the hippocampal areas. By focusing on the effects of APOE genotype on normal brain function, approaches can be pursued to identify biomarkers of APOE dysfunction, to promote normal functions of the APOE4 isoform, and to prevent the accumulation of the pathologic hallmarks of AD with aging.

Deciphering Isomers with a Multiple Reaction Monitoring Method for the Complete Detectable O-Glycan Repertoire of the Candidate Therapeutic, Lubricin.

Glycosylation is a fundamental post-translational modification, occurring on half of all proteins. Despite its significance, our understanding is limited, in part due to the inherent difficulty in studying these branched, multi-isomer structures. Accessible, detailed, and quantifiable methods for studying glycans, particularly O-glycans, are needed. Here we take a multiple reaction monitoring (MRM) approach to differentiate and relatively quantify all detectable glycans, including isomers, on the heavily O-glycosylated protein lubricin. Lubricin (proteoglycan 4) is essential for lubrication of the joint and eye. Given the therapeutic potential of lubricin, it is essential to understand its O-glycan repertoire in biological and recombinantly produced samples. O-Glycans were released by reductive ß-elimination and defined, showing a range of 26 neutral, sulfated, sialylated, and both sulfated and sialylated core 1 (Galß1-3GalNAcα1-) and core 2 (Galß1-3(GlcNAcß1-6)GalNAcα1-) structures. Isomer-specific MRM transitions allowed effective differentiation of neutral glycan isomers as well as sulfated isomeric structures, where the sulfate was retained on the fragment ions. This strategy was not as effective with labile sialylated structures; instead, it was observed that the optimal collision energy for the m/z 290.1 sialic acid B-fragment differed consistently between sialic acid isomers, allowing differentiation between isomers when fragmentation spectra were insufficient. This approach was also effective for purchased Neu5Acα2-3Galß1-4Glc and Neu5Acα2-6Galß1-4Glc and for Neu5Acα2-3Galß1-4GlcNAc and Neu5Acα2-6Galß1-4GlcNAc linkage isomers with the Neu5Acα2-6 consistently requiring more energy for optimal generation of the m/z 290.1 fragment. Overall, this method provides an effective and easily accessible approach for the quantification and annotation of complex released O-glycan samples.

Separation of Sialylated Glycan Isomers by Differential Mobility Spectrometry.

Mass spectrometry has proven itself to be an important technology for characterizing intact glycoproteins, glycopeptides, and released glycans. However, these molecules often present significant challenges during analysis. For example, glycans of identical molecular weights can be present in many isomeric forms, with one form having dramatically more biological activity than the others. Discriminating among these isomeric forms using mass spectrometry alone can be daunting, which is why orthogonal techniques, such as ion mobility spectrometry, have been explored. Here, we demonstrate the use of differential mobility spectrometry (DMS) to separate isomeric glycans differing only in the linkages of sialic acid groups (e.g., α 2,3 versus α 2,6). This ability extends from a small trisaccharide species to larger biantennary systems and is driven, in part, by the role of intramolecular solvation of the charge site(s) on these ions within the DMS environment.

Hydrogenolysis of Dinuclear PCNR Ligated PdII µ-Hydroxides and Their Mononuclear PdII Hydroxide Analogues.

The hydrogenolysis of mono- and dinuclear PdII hydroxides was investigated both experimentally and computationally. It was found that the dinuclear µ-hydroxide complexes {[(PCNR )Pd]2 (µ-OH)}(OTf) (PCNH =1-[3-[(di-tert-butylphosphino)methyl]phenyl]-1H-pyrazole; PCNMe =1-[3-[(di-tert-butylphosphino)methyl]phenyl]-5-methyl-1H-pyrazole) react with H2 to form the analogous dinuclear hydride species {[(PCNR )Pd]2 (µ-H)}(OTf). The dinuclear µ-hydride complexes were fully characterized, and are rare examples of structurally characterized unsupported singly bridged µ-H PdII dimers. The {[(PCNMe )Pd]2 (µ-OH)}(OTf) hydrogenolysis mechanism was investigated through experiments and computations. The hydrogenolysis of the mononuclear complex (PCNH )Pd-OH resulted in a mixed ligand dinuclear species [(PCNH )Pd](µ-H)[(PCC)Pd] (PCC=a dianionic version of PCNH bound through phosphorus P, aryl C, and pyrazole C atoms) generated from initial ligand "rollover" C-H activation. Further exposure to H2 yields the bisphosphine Pd0 complex Pd[(H)PCNH ]2 . When the ligand was protected at the pyrazole 5-position in the (PCNMe )Pd-OH complex, no hydride formed under the same conditions; the reaction proceeded directly to the bisphosphine Pd0 complex Pd[(H)PCNMe ]2 . Reaction mechanisms for the hydrogenolysis of the monomeric and dimeric hydroxides are proposed.

Reduced Mucin-7 (Muc7) Sialylation and Altered Saliva Rheology in Sjögren's Syndrome Associated Oral Dryness.

Sjögren's syndrome is a chronic autoimmune disorder characterized by lymphocytic infiltration and hypofunction of salivary and lacrimal glands. This loss of salivary function leads to oral dryness, impaired swallowing and speech, and increased infection and is associated with other autoimmune diseases and an increased risk of certain cancers. Despite the implications of this prevalent disease, diagnosis currently takes years, partly due to the diversity in patient presentation. Saliva is a complicated biological fluid with major constituents, including heavily glycosylated mucins MUC5B and MUC7, important for its viscoelastic and hydrating and lubricating properties. This study investigated Sjögren's patient's perception of dryness (bother index questionnaires) along with the rheological, protein composition, and glycan analysis of whole mouth saliva and the saliva on the mucosal surface (residual mucosal saliva) to understand the properties that most affect patient wellbeing. Sjögren's patients exhibited a statistically significant reduction in residual mucosal saliva, salivary flow rate, and extensional rheology, spinnbarkeit (stringiness). Although the concentration of mucins MUC5B and MUC7 were similar between patients and controls, a comparison of protein Western blotting and glycan staining identified a reduction in mucin glycosylation in Sjögren's, particularly on MUC7. LC-MS/MS analysis of O-glycans released from MUC7 by ß-elimination revealed that although patients had an increase in core 1 sulfation, the even larger reduction in sialylation resulted in a global decline of charged glycans. This was primarily due to the loss of the extended core 2 disialylated structure, with and without fucosylation. A decrease in the extended, fucosylated core 2 disialylated structure on MUC7, residual mucosal wetness, and whole mouth saliva flow rate appeared to have a negative and cumulative effect on the perception of oral dryness. The observed changes in MUC7 glycosylation could be a potential diagnostic tool for saliva quality and taken into consideration for future therapies for this multifactorial syndrome.

Single-Crystal and Electronic Structure of a 1.3 nm Indium Phosphide Nanocluster.

Magic-sized nanoclusters have been implicated as mechanistically relevant intermediates in the synthesis of group III-V quantum dots. Herein we report the single-crystal X-ray diffraction structure of a carboxylate-ligated indium phosphide magic-sized nanocluster at 0.83 Å resolution. The structure of this cluster, In37P20(O2CR)51, deviates from that of known crystal phases and possesses a non-stoichiometric, charged core composed of a series of fused 6-membered rings. The cluster is completely passivated by bidentate carboxylate ligands exhibiting predominantly bridging binding modes. The absorption spectrum of the cluster shows an asymmetric line shape that is broader than what would be expected from a homogeneous sample. A combination of computational and experimental evidence suggests that the spectral line width is a result of multiple, discrete electronic transitions that couple to vibrations of the nanocrystal lattice. The product of reaction of this nanocluster with 1 equiv of water has also been structurally characterized, demonstrating site selectivity without a drastic alteration of electronic structure.

The O-glycomap of lubricin, a novel mucin responsible for joint lubrication, identified by site-specific glycopeptide analysis.

The lubricative, heavily glycosylated mucin-like synovial glycoprotein lubricin has previously been observed to contain glycosylation changes related to rheumatoid and osteoarthritis. Thus, a site-specific investigation of the glycosylation of lubricin was undertaken, in order to further understand the pathological mechanisms involved in these diseases. Lubricin contains an serine/threonine/proline (STP)-rich domain composed of imperfect tandem repeats (EPAPTTPK), the target for O-glycosylation. In this study, using a liquid chromatography-tandem mass spectrometry approach, employing both collision-induced and electron-transfer dissociation fragmentation methods, we identified 185 O-glycopeptides within the STP-rich domain of human synovial lubricin. This showed that adjacent threonine residues within the central STP-rich region could be simultaneously and/or individually glycosylated. In addition to core 1 structures responsible for biolubrication, core 2 O-glycopeptides were also identified, indicating that lubricin glycosylation may have other roles. Investigation of the expression of polypeptide N-acetylgalactosaminyltransferase genes was carried out using cultured primary fibroblast-like synoviocytes, a cell type that expresses lubricin in vivo. This analysis showed high mRNA expression levels of the less understood polypeptide N-acetylgalactosaminyltransferase 15 and 5 in addition to the ubiquitously expressed polypeptide N-acetylgalactosaminyltransferase 1 and 2 genes. This suggests that there is a unique combination of transferase genes important for the O-glycosylation of lubricin. The site-specific glycopeptide analysis covered 82% of the protein sequence and showed that lubricin glycosylation displays both micro- and macroheterogeneity. The density of glycosylation was shown to be high: 168 sites of O-glycosylation, predominately sialylated, were identified. These glycosylation sites were focused in the central STP-rich region, giving the domain a negative charge. The more positively charged lysine and arginine residues in the N and C termini suggest that synovial lubricin exists as an amphoteric molecule. The identification of these unique properties of lubricin may provide insight into the important low-friction lubricating functions of lubricin during natural joint movement.

Validation of the curation pipeline of UniCarb-DB: building a global glycan reference MS/MS repository.

The UniCarb-DB database is an emerging public glycomics data repository, containing over 500 tandem mass spectra (as of March 2013) of glycans released from glycoproteins. A major challenge in glycomics research is to provide and maintain high-quality datasets that will offer the necessary diversity to support the development of accurate bioinformatics tools for data deposition and analysis. The role of UniCarb-DB, as an archival database, is to provide the glycomics community with open-access to a comprehensive LC MS/MS library of N- and O- linked glycans released from glycoproteins that have been annotated with glycosidic and cross-ring fragmentation ions, retention times, and associated experimental metadata descriptions. Here, we introduce the UniCarb-DB data submission pipeline and its practical application to construct a library of LC-MS/MS glycan standards that forms part of this database. In this context, an independent consortium of three laboratories was established to analyze the same 23 commercially available oligosaccharide standards, all by using graphitized carbon-liquid chromatography (LC) electrospray ionization (ESI) ion trap mass spectrometry in the negative ion mode. A dot product score was calculated for each spectrum in the three sets of data as a measure of the comparability that is necessary for use of such a collection in library-based spectral matching and glycan structural identification. The effects of charge state, de-isotoping and threshold levels on the quality of the input data are shown. The provision of well-characterized oligosaccharide fragmentation data provides the opportunity to identify determinants of specific glycan structures, and will contribute to the confidence level of algorithms that assign glycan structures to experimental MS/MS spectra. This article is part of a Special Issue entitled: Computational Proteomics in the Post-Identification Era. Guest Editors: Martin Eisenacher and Christian Stephan.

Selected reaction monitoring to differentiate and relatively quantitate isomers of sulfated and unsulfated core 1 O-glycans from salivary MUC7 protein in rheumatoid arthritis.

Rheumatoid arthritis is a common and debilitating systemic inflammatory condition affecting up to 1% of the world's population. This study aimed to investigate the immunological significance of O-glycans in chronic arthritis at a local and systemic level. O-Glycans released from synovial glycoproteins during acute and chronic arthritic conditions were compared and immune-reactive glycans identified. The sulfated core 1 O-glycan (Galß1-3GalNAcol) was immune reactive, showing a different isomeric profile in the two conditions. From acute reactive arthritis, three isomers could be sequenced, but in patients with chronic rheumatoid arthritis, only a single 3-Gal sulfate-linked isomer could be identified. The systemic significance of this glycan epitope was investigated using the salivary mucin MUC7 in patients with rheumatoid arthritis and normal controls. To analyze this low abundance glycan, a selected reaction monitoring (SRM) method was developed to differentiate and relatively quantitate the core 1 O-glycan and the sulfated core 1 O-glycan Gal- and GalNAc-linked isomers. The acquisition of highly sensitive full scan linear ion trap MS/MS spectra in addition to quantitative SRM data allowed the 3- and 6-linked Gal isomers to be differentiated. The method was used to relatively quantitate the core 1 glycans from MUC7 to identify any systemic changes in this carbohydrate epitope. A statistically significant increase in sulfation was identified in salivary MUC7 from rheumatoid arthritis patients. This suggests a potential role for this epitope in chronic inflammation. This study was able to develop an SRM approach to specifically identify and relatively quantitate sulfated core 1 isomers and the unsulfated structure. The expansion of this method may afford an avenue for the high throughput investigation of O-glycans.

Salivary mucin MUC7 oligosaccharides in patients with recurrent aphthous stomatitis.

OBJECTIVES: The aetiology of recurrent aphthous stomatitis remains unknown. In this study, we investigate the composition of oligosaccharides from mucin MUC7 in recurrent aphthous stomatitis as these heavily O-glycosylated mucins confer many of saliva's protective properties such as defence against mucosal pathogens. MATERIALS AND METHODS: Unstimulated whole saliva samples were collected from six individuals, three with recurrent aphthous stomatitis and three corresponding sibling, without this condition. Oligosaccharides from salivary MUC7 were isolated and analysed by liquid chromatography-tandem mass spectrometry. RESULTS: The types of oligosaccharides identified in the patients and control subjects were similar; however, statistical evaluation indicated semi-quantitative differences between specific oligosaccharide classes. These changes focused on a reduction in terminal glycan residues including fucosylation, sialylation and sulfation on galactose. CONCLUSIONS: This study was able to show differential MUC7 glycosylation in the patients suggesting functional changes to salivary mucins in this condition. The terminal glycans altered in disease have been shown to be important for a range of immunological and bacterial binding roles. Further investigation of these epitopes in a larger study may provide critical insights into the pathology of recurrent aphthous stomatitis. CLINICAL RELEVANCE: MUC7 glycosylation is altered in recurrent aphthous stomatitis. This may change the protective properties of this mucin against mucosal pathogens, which may effect this condition.

Compassionate Care: A Qualitative Exploration of Nurses' Inner Resources in the Face of Burnout.

There is a universal shortage of nurses, with a current needs-based shortage of 5.9 million. This is not solely a recruitment issue but one of retention, triggered by high levels of work-induced stress, burnout, and reports of low job satisfaction resulting in poor care delivery. Some of the health repercussions on nurses include anxiety, insomnia, depression, migraines, irritability, absenteeism, and sometimes alcoholism and drug abuse. To tackle some of these costly issues, a qualitative exploration into how inner resources is used by nurses to cope with stress at different points of their careers is proposed. Through the lens of grounded theory, semi-structured interviews will be carried out with two distinct sets of participants: (1) Student nurses registered at the University of the Illes Baleares between 2022-2025. (2) Experienced nurses on the Balearic nursing register. Interviews will be coded and then analysed using Atlas.ti. Expected results will inform curriculum improvements that will benefit the well-being of (student) nurses, from the outset of their training, pre-empting potential psycho-social risks before they arise in the workplace. This is vital as it addresses nurses' mental health as well as chronic issues of retention and absenteeism.

Protocol for a seamless phase 2A-phase 2B randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of benfotiamine in patients with early Alzheimer's disease (BenfoTeam).

BACKGROUND: Benfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches. OBJECTIVE: To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD. METHODS: This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA. CONCLUSION: The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.

Uncovering the dominant role of root metabolism in shaping rhizosphere metabolome under drought in tropical rainforest plants.

Plant-soil-microbe interactions are crucial for driving rhizosphere processes that contribute to metabolite turnover and nutrient cycling. With the increasing frequency and severity of water scarcity due to climate warming, understanding how plant-mediated processes, such as root exudation, influence soil organic matter turnover in the rhizosphere is essential. In this study, we used 16S rRNA gene amplicon sequencing, rhizosphere metabolomics, and position-specific 13C-pyruvate labeling to examine the effects of three different plant species (Piper auritum, Hibiscus rosa sinensis, and Clitoria fairchildiana) and their associated microbial communities on soil organic carbon turnover in the rhizosphere. Our findings indicate that in these tropical plants, the rhizosphere metabolome is primarily shaped by the response of roots to drought rather than direct shifts in the rhizosphere bacterial community composition. Specifically, the reduced exudation of plant roots had a notable effect on the metabolome of the rhizosphere of P. auritum, with less reliance on neighboring microbes. Contrary to P. auritum, H. rosa sinensis and C. fairchildiana experienced changes in their exudate composition during drought, causing alterations to the bacterial communities in the rhizosphere. This, in turn, had a collective impact on the rhizosphere's metabolome. Furthermore, the exclusion of phylogenetically distant microbes from the rhizosphere led to shifts in its metabolome. Additionally, C. fairchildiana appeared to be associated with only a subset of symbiotic bacteria under drought conditions. These results indicate that plant species-specific microbial interactions systematically change with the root metabolome. As roots respond to drought, their associated microbial communities adapt, potentially reinforcing the drought tolerance strategies of plant roots. These findings have significant implications for maintaining plant health and preference during drought stress and improving plant performance under climate change.

The Spanish Version of the State Self-Compassion Scale-Long Form (SSCS-L): A Study of Its Validity and Reliability in a Sample of Nursing Students.

BACKGROUND: In nurses, self-compassion mitigates the effects of stress, burnout and compassion fatigue, and enhances empathy, compassion and well-being and quality of life. The Self-Compassion Scale is the most-used instrument. The aim of this study is to validate the Spanish version of the new developed State Self-Compassion Scale-Long (SSCS-L). METHODS: Students of the first year of the Nursing Degree were surveyed online. Together with the SSCS-L, their levels of positive and negative affect was reported. Analyses included descriptive statistics, competitive confirmatory factor analysis, evidence on criterion-related validity and estimates of reliability. RESULTS: The best fitting model for the SSCS-L was the one hypothesizing six-correlated factors of self-compassion: self-kindness, common humanity, mindfulness, self-judgement, isolation, and over-identification. Positive relations between the positive dimensions of self-compassion and positive affect were found, whereas there were negative relations between the positive poles of self-compassion and negative affect. Estimates of reliability were adequate, except for the dimension of over-identification. CONCLUSIONS: Self-compassion has become a key competency for nurses. The SSCS-L is an appropriate tool to allow an adequate assessment of self-compassion in experimental contexts.

Pharmacological thiamine levels as a therapeutic approach in Alzheimer's disease.

of the study.