bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multimorbidity Management: A scoping review of comprehensive interventions for multimorbidity outcomes
Authors: Seakamela Kagiso P , Mashaba Reneilwe G , Ntimana Cairo B , Kabudula Chodziwadziwa W , Sodi Tholene 
Published: January 2025

AbstractBackgroundMultimorbidity, defined as the co-occurrence of two or more chronic conditions in an individual, has emerged as a worldwide public health concern contributing to mortality and morbidity. With a prevalence estimated at 37% globally, this complex health phenomenon is increasingly affecting populations as they age. Despite the growing burden of multimorbidity, the development and implementation of interventions published by scholars are still in their early stages with significant variability in strategies and outcomes.ObjectivesThe review aims to synthesize interventions designed to manage and mitigate multimorbidity and explore a range of approaches, including pharmacological treatments, lifestyle modifications, care coordination models, and technological innovations.MethodsThe scoping review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist. It included about 1,227,906 individuals with multimorbidity, with 199,413 being male (16.2%) and 1,028,493 (83.8%) female participants. Multimorbidity interventions were defined as strategies or programs designed to manage and improve the health and quality of life of individuals with multiple chronic conditions.ResultsThe final analysis included 101 articles from 3119 published between 2012 and 2024. Themes on the need for lifestyle and behavioural interventions, patient empowerment and engagement, multimorbidity management, health integration, pharmacotherapy optimization, community and policy interventions, healthcare system improvements, technology and digital health, as well as research and evidence-based practice interventions, emerged.ConclusionThe reviewed literature emphasizes the necessity of multidisciplinary approaches to effectively combat the escalating pandemic of multimorbidity.
Program Cost and Return on Investment of a Remote Patient Monitoring Program for Hypertension Management
Authors: Zhang Donglan Stacy , Millet Laure , Bellows Brandon K. , Lee Sarah , Mann Devin 
Published: January 2025

ABSTRACTObjectiveTo evaluate the program costs and financial sustainability of a remote patient monitoring for hypertension (RPM-HTN) program implemented in the cardiology practice of a large healthcare system.Study DesignThis economic evaluation utilized field observation, interviews, literature review, and quantitative analysis to assess RPM-HTN from March to June 2024 at New York University Langone HealthMethodsA costing tool was developed to quantify program costs, including personnel, start-up, equipment, and supply expenses, expressed in 2024 USD. Reimbursement rates were estimated using the 2024 Medicare Physician Fee Schedule. The return on investment (ROI) was calculated as the ratio of net return to program costs. Univariate sensitivity analyses evaluated the impact of varying a single parameter at a time on ROI.ResultsThe average cost of RPM-HTN was $330 per patient (range: $208–$452), with an annual program cost of $33,000 (range: $20,785–$45,168) for 100 patients enrolled from the Cardiology Division. Key expenses included data review by nurse practitioners ($172/patient), blood pressure device costs ($48/patient), and nurse-patient communication ($36/patient). ROI averaged 22.2% at 55% patient compliance with the RPM-HTN program. This ROI ranged from-11.1% (assuming program costs of $452) to 93.3% (assuming program costs of $208) per patient. ROI was most sensitive to changes in data review costs, insurance reimbursement, patient compliance, and device setup.ConclusionsThe RPM-HTN program demonstrated positive ROI, indicating financial sustainability in a large urban healthcare system. Improving patient compliance with the program and reducing human resource costs are critical for scaling RPM-HTN programs effectively.
Lethal streptococcal infection is associated with widened lymph node bottlenecks
Authors: Xia Linya , Hullahalli Karthik , Tian Xingyu , Yuan Chen , Pan Fei , Fan Hongjie , Waldor Matthew K. , Ma Zhe 
Published: January 2025

AbstractStreptococcus suisserotype 2 (SS2) infection causes streptococcal toxic shock-like syndrome (STSLS), which can be lethal in both pigs and humans. In mouse models, relatively subtle differences in the inoculum size result in drastically different infection outcomes, from clearance to acute death. Here, we leveraged barcoded SS2 in a murine model to define the bacterial population dynamics associated with death. Barcode sequencing analysis demonstrated that a 10-fold increase in inoculum size led to a 100-1,000-fold increase in the number of bacteria that initiated infection in certain lymph nodes, ultimately driving lethality. This lethal dose threshold was in part driven by suilysin (SLY), the major SS2 virulence factor. At higher doses, the clearance and replication kinetics of bacteria lacking SLY mimicked WT SS2 at sub-lethal doses. Our findings suggest that acute death in SS2 infection is caused by a wholesale failure of the immune system, enabling a large number of bacteria to initiate infection. These results demonstrate how subtle changes in inoculum size can have dramatic consequences for infection outcome and how lethal infection is driven by widened infection bottlenecks.Author SummaryLethal infections are often associated with a specific dose threshold, where increasing inoculum size is associated with an increased likelihood of death. However, a quantitative explanation how this numeric threshold is established is lacking. For example, lethal dose thresholds may reflect a dose where at least one microbe can pass through host-imposed barriers to infection. Alternatively, lethal dose thresholds may reflect a failure of the host immune system, leading to numerous microbes initiating infection. Here, using barcodedStreptococcus suisserotype 2 (SS2), we compare the within-host population dynamics associated between lethal and non-lethal infections. We find that lethal doses are associated with dramatic widening of infection bottlenecks, leading to a large number of bacteria that initiate infection. Lethal infection is also driven by suilysin, the major SS2 virulence factor. These observations demonstrate how lethal doses are quantitatively established by the relationship between host bottlenecks and bacterial virulence factors.
Clostridioides difficilemajor toxins remodel the intestinal epithelia, affecting spore adherence/internalization into intestinal tissue and their association with gut vitronectin
Authors: Castro-Cordova Pablo , Lopez-Garcia Osiris K. , Orozco Josué , Montes-Bravo Nicolás , Gil Fernando , Pizarro-Guajardo Marjorie , Paredes-Sabja Daniel 
Published: January 2025

AbstractThe most common cause of healthcare-associated diarrhea and colitis in the U.S., isClostridioides difficile, a spore-forming pathogen. Two toxins, TcdA and TcdB, are major virulence factors essential for disease manifestations, whileC. difficilespores are essential for disease transmission and recurrence. Both toxins cause major damage to the epithelial barrier, trigger massive inflammation, and reshape the microbiome and metabolic composition, facilitatingC. difficilecolonization.C. difficilespores, essential for transmission and recurrence of the disease, persist adhered and internalized in the intestinal epithelia. Studies have suggested that toxin-neutralization in combination with antibiotic during CDI treatment in humans significantly reduces disease recurrence, suggesting a link between toxin-mediated damage and spore persistence. Here, we show that TcdA/TcdB-intoxication of intestinal epithelial Caco-2 cells leads to remodeling of accessible levels of fibronectin (Fn) and vitronectin (Vn) and their cognate alpha-integrin subunits. While TcdB-intoxication of intestinal tissue had no impact in accessible levels of Fn and Vn, but significantly increased levels of intracellular Vn. We observed that Fn and Vn released to the supernatant readily bind toC. difficilesporesin vitro, while TcdB-intoxication of intestinal tissue led to increased association ofC. difficilespores with gut Vn. Toxin-intoxication of the intestinal tissue also contributes to increased adherence and internalization ofC. difficilespores. However, TcdB-intoxicated ligated loops infected of mice treated with Bezlotoxumanb (monoclonal anti- TcdB antibodies) did not prevent TcdB-mediated increased spore adherence and internalization into intestinal tissue. This study highlights the importance of studying the impact ofC. difficiletoxins of host tissues has inC. difficileinteraction with host surfaces that may contribute to increased persistence and disease recurrence.
Interface integrity in septin protofilaments is maintained by an arginine residue conserved from yeast to man
Authors: Grupp Benjamin , Graser Jano Benito , Seifermann Julia , Gerhardt Stefan , Lemkul Justin A. , Gehrke Jan Felix , Johnsson Nils , Gronemeyer Thomas 
Published: January 2025

AbstractThe septins are conserved, filament-forming, guanine nucleotide binding cytoskeletal proteins. They assemble into palindromic protofilaments which polymerize further into higher-ordered structures that participate in essential intracellular processes such as cytokinesis or polarity establishment. Septins belong structurally to the P-Loop NTPases but, unlike their relatives Ras or Rho, do not mediate signals to effectors through GTP binding and hydrolysis. Biochemical approaches addressing how and why septins utilize nucleotides are hampered by the lack of nucleotide free complexes. Using molecular dynamics simulations, we determined structural alterations and inter-subunit binding free energies in human and yeast septin dimer structures and in theirin silicogenerated apo forms.An interchain saltbridge network in the septin unique β-meander, conserved across all kingdoms of septin containing species, is destabilized upon nucleotide removal, concomitant with disruption of the entire G-interface.Within this network, we identified a conserved arginine residue, Arg(βb), as the central interaction hub.The essential role of Arg(βb) for interface integrity was confirmed species-overlapping in human and yeast septins byin vitroandin vivoexperimentation.
Speech-in-noise discriminability after noise exposure: Insights from a gerbil model of acoustic trauma
Authors: Jüchter Carolin , Beutelmann Rainer , Klump Georg Martin 
Published: January 2025

AbstractExposure to loud sounds can lead to hearing impairments. Speech comprehension, especially in the presence of background sounds, allegedly declines as a consequence of noise-induced hearing loss. However, the connection between noise overexposure and deteriorated speech-in-noise perception is not clear yet and potential underlying mechanisms are still under debate. This study investigates speech-in-noise discrimination in young-adult Mongolian gerbils before and after an acoustic trauma to reveal possible noise-induced changes in the perception of speech sounds and to examine the commonly suggested link between noise exposure and speech-in-noise perception difficulties. Nine young-adult gerbils were trained to discriminate a deviant consonant-vowel-consonant combination (CVC) or vowel-consonant-vowel combination (VCV) in a sequence of CVC or VCV standards, respectively. The logatomes were spoken by different speakers and masked by a steady-state speech-shaped noise. After the gerbils completed the behavioral baseline experiments, they underwent an acoustic trauma and collected data for the second time in the behavioral experiments. Applying multidimensional scaling, response latencies were used to generate perceptual maps reflecting the gerbils’ internal representations of the sounds pre- and post-trauma. To evaluate how the discrimination of vowels and consonants was altered after the acoustic trauma, changes in response latencies between phoneme pairs were investigated with regard to their articulatory features. Auditory brainstem responses were measured to assess peripheral auditory function. We found that the perceptual maps of vowels and consonants were very similar before and after noise exposure. Interestingly, the gerbils’ overall vowel discrimination ability was improved after the acoustic trauma, even though the gerbils suffered from noise-induced hearing loss. In contrast to the improvements in vowel discrimination, there were only minor changes in the gerbils’ ability to discriminate consonants. Moreover, the noise exposure showed a differential influence on the response latencies for vowel and consonant discriminations depending on the articulatory features of the specific phonemes.
Infection and herbicide exposure implicate c-Abl kinase in α-Synuclein Ser129 phosphorylation
Authors: Ehsani Marzieh , Sun Zeyang , Quevedo-Olmos Alvaro , Rösler Gesa , Rasa Mahdi , Holthaus David , Erttmann Saskia F. , Meyer Thomas F. 
Published: January 2025

AbstractBackgroundParkinson’s disease is a complex multifactorial neurodegenerative disorder characterized by α-Synuclein aggregation in Lewy bodies, with phosphorylation at serine 129 (pSer129) being a critical pathological hallmark. However, the exact mechanisms by which environmental triggers lead to this disease phenotype remain poorly understood. In this study we compare the effects of an exemplary infection and a certain pesticide exposure on the generation of pSer129 α-Synuclein, with a focus on the involvement of cellular kinases in this process.MethodsTwo distinct environmental stressors were applied to neuronal cells: the pesticide rotenone and the well-studied gastric bacteriumHelicobacter pylori (H. pylori). Phosphorylation of Ser129 α-Synuclein was assessed by immunofluorescent staining and Western blotting. Cells were treated with mechanistically distinct c-Abl inhibitors, and pSer129 α-Synuclein was detected using Western blotting and activities of the upstream serine-threonine kinase were predicted by kinase profiling and Western blotting, analyzed by one-way ANOVA followed by Tukey’s multiple comparisons test. Moreover, transcriptome analyses of treated cells were performed and ingenuity pathway analysis and Deseq2 were applied to unravel the affected neurodegenerative pathways.ResultsThe functional analysis of our RNA sequence data demonstrated that bothH. pyloriand rotenone induced oxidative stress and neuroinflammation by stimulating neurodegenerative pathways. Rotenone andH. pyloriactivated c-Abl, likely through the induced oxidative stress and promoted α-Synuclein phosphorylation. The kinase inhibitors Ponatinib and Asciminib effectively prevented pSer129 α-Synuclein accumulation and reversed associated gene expression changes induced by rotenone orH. pylori. Moreover, GSK3β appeared to be involved in the induction of Ser129 phosphorylation via activated c-Abl. Furthermore,H. pylori’svacuolating cytotoxin appeared to play a crucial role in the phosphorylation of pSer129 α-Synuclein by c-Abl.ConclusionsThese findings highlight the pivotal role of c-Abl in α-Synucleopathies and provide insights into shared mechanisms between infection and pesticide exposure, offering potential therapeutic targets for Parkinson’s disease and related pathologies involving α-Synuclein modification.
Aggregated A-synuclein leads to corticostriatal synaptic dysfunction
Authors: Brzozowski Charlotte F. , Challa Harshita , Gcwensa Nolwazi Z. , Hall Dominic , Nabert Douglas , Chambers Nicole , Gallardo Ignacio , Millet Michael , Volpicelli-Daley Laura , Moehle Mark S. 
Published: January 2025

AbstractNeuronal inclusions of α-synuclein (α-syn) are pathological hallmarks of Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB). α-Syn pathology accumulates in cortical neurons which project to the striatum. To begin to understand how α-syn pathology effects cortico-striatal synapses, pre-formed α-syn fibrils (PFF) were injected into the striatum to induce robust α-syn aggregation in corticostriatal-projecting neurons. Electrophysiological recordings of striatal spiny projection neurons (SPNs) acute slices found a significant decrease in evoked corticostriatal glutamate release in mice with PFF-induced aggregates compared to monomer injected mice. Expansion microscopy, confocal microscopy and Imaris reconstructions were used to identify vGLUT1 positive presynaptic terminals juxtaposed to Homer-positive postsynaptic densities, termed synaptic foci. Quantitation of synaptic loci density revealed a loss of corticostriatal synapses. Immunoblots of the striatum show reductions in expression of pre-synaptic proteins with selective reduction in AMPA and NMDA receptor subunits in mice with α-syn aggregates compared to controls. Paradoxically, a small percentage of remaining VLGUT1+ synaptic loci with small, intrasynaptic α-syn aggregates showed enlarged volumes compared to nearby synapses without α-syn aggregates. Our combined physiology and high-resolution imaging data point to dysfunction of corticostriatal synapses in mice harboring □-synuclein inclusions, which may contribute to impaired basal ganglia circuitry in PD.Highlights- Corticostriatal glutamate drive is impaired in the presence of pathological α-syn- α-Syn aggregation causes early loss of corticostriatal synapses- Synaptic loci positive for small α-syn aggregates show volume increases- Striatal expression of select synaptic proteins are reduced in animals with α-syn pathology
Profiling trait and state-like behaviour in pain modulation systems: a role for effective connectivity within endogenous pain control circuits
Authors: Medina Sonia , Clarke Sophie , Hughes Sam W. 
Published: January 2025

AbstractEndogenous pain modulation systems can be assessed through distinct psychophysical paradigms such as conditioned pain modulation (CPM), temporal summation of pain (TSP), and offset analgesia (OA). Notably, the reliability of these measures has rarely been defined within the same participants, and measures to index the consistency of each measure across sessions and in the same participants are lacking. This study examined the test-retest reliability and intra-individual consistency of CPM, TSP, and OA and explored how CPM response status across sessions relates to neural dynamics within the descending pain modulation system. In 29 healthy participants, CPM, TSP, and OA responses were assessed across two sessions. The normalised session change index (NSCI) was introduced to evaluate consistency of each measure across sessions. Spectral dynamic causal modelling (DCM) of resting-state fMRI (rs-fMRI) investigated effective connectivity within the descending pain modulation network and its association with CPM response status. OA exhibited the highest test-retest reliability and had NSCI values closest to zero, indicating stable responses. CPM and TSP showed poor reliability and NSCI values deviating from zero, reflecting greater variability. Spectral DCM analysis revealed that effective connectivity within the descending pain modulation system explained CPM response variability across sessions. Specifically, consistent strong facilitatory or inhibitory CPM was associated with greater excitatory or inhibitory PAG-to-AI effective connectivity, respectively. These findings suggest that healthy participants either demonstrate stable (i.e. trait-like) or dynamic (i.e. state-like) endogenous pain modulation across repeated sessions which can be explained based on effective connectivity within the descending pain modulation system.
In-silico molecular enrichment and clearance of the human intracranial space
Authors: Causemann Marius , Kuchta Miroslav , Masri Rami , Rognes Marie E. 
Published: January 2025

ABSTRACTThe mechanisms of intracranial solute transport are fundamental to human brain health, with alterations often linked to disease and functional impairment, and with distinct opportunities for personalized diagnostics and treatment. However, our understanding of these mechanisms and their interplay remains incomplete, in part due to the complexity of integrating insights across scales, between species and from different modalities. Here, we combine mixed-dimensional modelling, multi-modal magnetic resonance images, and high performance computing to construct and explore a high-fidelity in-silico model of human intracranial molecular enrichment. This model predicts the temporo-spatial spreading of a solute within an image-derived geometric representation of the subarachnoid space, ventricular system and brain parenchyma, including networks of surface perivascular spaces (PVSs). Our findings highlight the significant impact of cerebrospinal fluid (CSF) production and intracranial pulsatility on molecular enrichment following intrathecal tracer injection. We demonstrate that low-frequency vasomotion induces moderate CSF flow in surface PVS networks which substantially enhances tracer enrichment, and that impaired enrichment is a direct natural consequence of enlarged PVSs. This openly available technology platform thus provides an opportunity for integrating separate observations on diffusion in neuropil, vascular dynamics, intracranial pulsatility, CSF production, and efflux, and for exploring drug delivery and clearance in the human brain.
Investigating the influence of experimentally induced central sensitisation on pain prediction error encoding in healthy individuals: a novel virtual reality protocol
Authors: Palmisani Federico , Thiyagarajan Jawahar Sri Prakash , Horsey Joe , Hughes Sam , Medina Sonia 
Published: January 2025

AbstractPersistent mismatches between predicted and actual pain-related signals, namely prediction errors (PEs), can cause maladaptive overestimation of pain intensity, a common feature of chronic pain states. Experimental protocols used to assess the contribution of central sensitisation (CS) to dysregulated prediction systems are lacking. To address this, we implemented a novel virtual reality (VR) paradigm to evoke PEs during mechanical stimulation following experimentally induced CS via the high-frequency stimulation (HFS) model. Twenty healthy volunteers underwent HFS on the right forearm. Mechanical pain sensitivity (MPS) was assessed through pinprick stimuli before and 30 minutes post-HFS to evaluate secondary hyperalgesia. Following this, participants received mechanical stimuli at proximal (sensitised area) and distal (non-sensitised area) points from the HFS site, with visual cues presented on their arm via VR alongside hand tracking technology indicating the stimulus location, allowing participants to make pain predictions. Cues were either congruent (matching) or incongruent (mismatching) with the actual stimulus site, to evoke PEs. Results showed that MPS significantly increased following HFS, confirming secondary hyperalgesia. Stimuli in sensitised areas induced more pain than in non-sensitised areas. Incongruent cues successfully elicited PEs across all locations, however, expectations modulated pain perception only in non-sensitised areas. Similarly, during incongruent trials, PEs diminished over time (reflecting adaptive learning) only in non-sensitised areas. These data demonstrate that pain expectations can influence pain perception differently in centrally sensitised and non-sensitised states. We propose this protocol as a good candidate to assess how cognitive and psychological manipulations influence PEs at various stages of CS.