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1.
Ann Rev Mar Sci ; 2024 Sep 11.
Article de Anglais | MEDLINE | ID: mdl-39259980

RÉSUMÉ

The impact of saltwater intrusion on coastal forests and farmland is typically understood as sea-level-driven inundation of a static terrestrial landscape, where ecosystems neither adapt to nor influence saltwater intrusion. Yet recent observations of tree mortality and reduced crop yields have inspired new process-based research into the hydrologic, geomorphic, biotic, and anthropogenic mechanisms involved. We review several negative feedbacks that help stabilize ecosystems in the early stages of salinity stress (e.g., reduced water use and resource competition in surviving trees, soil accretion, and farmland management). However, processes that reduce salinity are often accompanied by increases in hypoxia and other changes that may amplify saltwater intrusion and vegetation shifts after a threshold is exceeded (e.g., subsidence following tree root mortality). This conceptual framework helps explain observed rates of vegetation change that are less than predicted for a static landscape while recognizing the inevitability of large-scale change.

2.
J Am Chem Soc ; 2024 Sep 10.
Article de Anglais | MEDLINE | ID: mdl-39255453

RÉSUMÉ

Cells contain intricate protein nanostructures, but replicating them outside of cells presents challenges. One such example is the vertical fibronectin pillars observed in embryos. Here, we demonstrate the creation of cell-free vertical fibronectin pillar mimics using nonequilibrium self-assembly. Our approach utilizes enzyme-responsive phosphopeptides that assemble into nanotubes. Enzyme action triggers shape changes in peptide assemblies, driving the vertical growth of protein nanopillars into bundles. These bundles, with peptide nanotubes serving as a template to remodel fibronectin, can then recruit collagen, which forms aggregates or bundles depending on their types. Nanopillar formation relies on enzyme-catalyzed nonequilibrium self-assembly and is governed by the concentrations of enzyme, protein, peptide, the structure of the peptide, and peptide assembly morphologies. Cryo-EM reveals unexpected nanotube thinning and packing after dephosphorylation, indicating a complex sculpting process during assembly. Our study demonstrates a cell-free method for constructing intricate, multiprotein nanostructures with directionality and composition.

3.
Rev Sci Tech ; 43: 87-95, 2024 Aug.
Article de Anglais | MEDLINE | ID: mdl-39222108

RÉSUMÉ

In a world characterised by data deserts and data swamps, translating evidence into actionable policies and practices is not easy. This article addresses this challenge through the lens of evidence emerging from the Global Burden of Animal Diseases (GBADs) initiative. It emphasises the need for an intentional approach that connects research information with the specific needs of decision-makers and identifies specific impact pathways associated with different groups of decision-makers. The GBADs programme aims to support animal health decisions, and the authors outline the diverse landscape of decision-makers in this field, encompassing the public and private sectors, livestock keepers, civil society and international development agencies. Key issues such as disease prioritisation and lobbying are also discussed. The authors propose an â€Ëœevidence ecosystem'approach, one that understands data users and their interactions, for analysing the needs of decision-makers, and framing GBADs offerings according to these needs. Two case studies, a recently concluded global case study of disease prioritisation decision-making and an ongoing policy analysis and needs assessment for GBADs in Indonesia, are presented to demonstrate how evidence ecosystem analysis and audience segmentation could be used to tailor GBADs information offerings for different decision-making groups. The article concludes by recommending that GBADs'future applications prioritise information offerings, adapt them to decision-makers'needs and consider how different segments of decision-makers will utilise the information to achieve real-world impacts.


Dans un monde où l'on rencontre aussi bien des déserts de données que des marécages de données, il n'est guère facile d'utiliser avec succès des données probantes pour les traduire en politiques et en pratiques exploitables. Les auteurs abordent cette difficulté dans l'optique des données actuellement générées dans le cadre de l'initiative " Impact mondial des maladies animales " (GBADs). Ils soulignent l'importance de disposer d'une méthode volontariste capable de relier l'information issue de la recherche avec les besoins spécifiques des décideurs, en tenant compte des chemins d'impact spécifiques associés à chaque catégorie de décideurs. Le programme GBADs vise à soutenir les décisions relatives à la santé animale ; les auteurs donnent une vue d'ensemble de la diversité des décideurs intervenant dans ce domaine, qui recouvre les secteurs public et privé, les éleveurs, la société civile et les organismes internationaux de développement. Certaines questions majeures comme le classement des maladies par ordre de priorité et les activités des groupes de pression sont également abordées. Afin de pouvoir analyser les besoins de ces décideurs et d'encadrer les propositions du GBADs en conséquence, les auteurs proposent une approche qualifiée d'" écosystème d'éléments probants ", qui permet de comprendre les utilisateurs de données et leurs interactions. À travers deux études de cas, l'une récemment achevée sur l'établissement des priorités sanitaires dans les prises de décision à l'échelle mondiale et l'autre actuellement en cours sur l'analyse des politiques et l'évaluation des besoins dans le cadre du GBADs en Indonésie, les auteurs démontrent comment l'analyse de l'écosystème d'éléments probants et la segmentation des destinataires permettent de moduler les informations proposées par le GBADs en fonction des différents groupes de décideurs auxquels elle sont destinées. Les auteurs concluent en recommandant que les applications futures du GBADs établissent des priorités parmi les informations proposées, en les adaptant aux besoins des décideurs et en considérant le nombre de segments différents de décideurs qui vont utiliser l'information en vue de résultats tangibles.


En un mundo caracterizado por los desiertos y los pantanos de datos, no es una misión fácil traducir los datos en políticas y prácticas viables. Este artículo aborda este reto desde la óptica de los datos procedentes de la iniciativa sobre el impacto global de las enfermedades animales (GBADs). Asimismo, subraya la necesidad de un planteamiento intencionado que conecte la información de las investigaciones con las necesidades específicas de los responsables de la toma de decisiones e identifique vías de impacto concretas asociadas a los distintos grupos de decisores. El programa del GBADs busca respaldar las decisiones en materia de sanidad animal y, a este respecto, los autores del artículo describen la diversidad de responsables de la toma de decisiones en dicho ámbito, entre los que figuran los sectores público y privado, los ganaderos, la sociedad civil y los organismos internacionales de desarrollo. También se abordan cuestiones clave como la priorización de enfermedades y los grupos de presión. Los autores proponen un enfoque basado en un "ecosistema de datos" que tenga en cuenta a los usuarios de los datos y sus interacciones a fin de analizar las necesidades de los responsables de la toma de decisiones y enmarcar los servicios del GBADs en función de dichas necesidades. Se presentan dos estudios de casos, uno mundial sobre la toma de decisiones en materia de priorización de enfermedades, que concluyó recientemente, y otro en curso sobre análisis de políticas y evaluación de necesidades del GBADs en Indonesia, con miras a demostrar cómo el análisis del ecosistema de datos y la segmentación de la audiencia podrían utilizarse para adaptar los servicios de información del GBADs a los distintos grupos de responsables de la toma de decisiones. El artículo concluye recomendando que las futuras aplicaciones del GBADs prioricen los servicios de información, los adapten a las necesidades de los responsables de la toma de decisiones y tengan en cuenta cómo utilizarán la información los distintos grupos de responsables para lograr repercusiones en el mundo real.


Sujet(s)
Maladies de l'animal , Prise de décision , Animaux , Maladies de l'animal/épidémiologie , Maladies de l'animal/prévention et contrôle , Humains , Santé mondiale , Charge mondiale de morbidité
4.
Sci Rep ; 14(1): 18401, 2024 08 08.
Article de Anglais | MEDLINE | ID: mdl-39117664

RÉSUMÉ

Image-based deformation estimation is an important tool used in a variety of engineering problems, including crack propagation, fracture, and fatigue failure. These tools have been important in biomechanics research where measuring in vitro and in vivo tissue deformations are important for evaluating tissue health and disease progression. However, accurately measuring tissue deformation in vivo is particularly challenging due to limited image signal-to-noise ratio. Therefore, we created a novel deep-learning approach for measuring deformation from a sequence of images collected in vivo called StrainNet. Utilizing a training dataset that incorporates image artifacts, StrainNet was designed to maximize performance in challenging, in vivo settings. Artificially generated image sequences of human flexor tendons undergoing known deformations were used to compare benchmark StrainNet against two conventional image-based strain measurement techniques. StrainNet outperformed the traditional techniques by nearly 90%. High-frequency ultrasound imaging was then used to acquire images of the flexor tendons engaged during contraction. Only StrainNet was able to track tissue deformations under the in vivo test conditions. Findings revealed strong correlations between tendon deformation and applied forces, highlighting the potential for StrainNet to be a valuable tool for assessing rehabilitation strategies or disease progression. Additionally, by using real-world data to train our model, StrainNet was able to generalize and reveal important relationships between the effort exerted by the participant and tendon mechanics. Overall, StrainNet demonstrated the effectiveness of using deep learning for image-based strain analysis in vivo.


Sujet(s)
Apprentissage profond , Tendons , Échographie , Tendons/imagerie diagnostique , Tendons/physiologie , Humains , Échographie/méthodes , Phénomènes biomécaniques , Traitement d'image par ordinateur/méthodes
5.
Sci Rep ; 14(1): 19734, 2024 08 26.
Article de Anglais | MEDLINE | ID: mdl-39183360

RÉSUMÉ

Dayak tribes indigenous to the Indonesian island of Borneo has been using Bajakah Kalalawit (Uncaria gambir Roxb.) as traditional medicine for ages. This inspired us to develop phenolic from Bajakah Kalalawit extract as antibacterial agent. The extraction was done through decoction method and the determination of phenolic concentration was done using a visible spectrophotometer and Folin-Ciocalteu reagent (mixture of phosphotungstic and phosphomolybdic acids). We investigated the possibility of developing phenolic nanoparticle for future work. Kirby-Bauer method was used to assess antibacterial activity of phenolic against Staphylococcus aureus and the results were compared to Chloramphenicol in terms of its efficacy and duration of inhibition. This study contributes to the ongoing effort to address antibiotic resistance through the development of innovative antibacterial agents derived from natural sources. The results provide valuable insights into the potential of Bajakah Kalalawit phenolic extracts as a promising avenue for combating bacterial infections in the future.


Sujet(s)
Antibactériens , Tests de sensibilité microbienne , Nanoparticules , Phénols , Extraits de plantes , Staphylococcus aureus , Staphylococcus aureus/effets des médicaments et des substances chimiques , Antibactériens/pharmacologie , Antibactériens/composition chimique , Nanoparticules/composition chimique , Extraits de plantes/pharmacologie , Extraits de plantes/composition chimique , Phénols/pharmacologie , Phénols/composition chimique , Indonésie
6.
Emerg Infect Dis ; 30(8): 1599-1608, 2024 Aug.
Article de Anglais | MEDLINE | ID: mdl-39043406

RÉSUMÉ

Bacterial zoonoses are established causes of severe febrile illness in East Africa. Within a fever etiology study, we applied a high-throughput 16S rRNA metagenomic assay validated for detecting bacterial zoonotic pathogens. We enrolled febrile patients admitted to 2 referral hospitals in Moshi, Tanzania, during September 2007-April 2009. Among 788 participants, median age was 20 (interquartile range 2-38) years. We performed PCR amplification of V1-V2 variable region 16S rRNA on cell pellet DNA, then metagenomic deep-sequencing and pathogenic taxonomic identification. We detected bacterial zoonotic pathogens in 10 (1.3%) samples: 3 with Rickettsia typhi, 1 R. conorii, 2 Bartonella quintana, 2 pathogenic Leptospira spp., and 1 Coxiella burnetii. One other sample had reads matching a Neoerhlichia spp. previously identified in a patient from South Africa. Our findings indicate that targeted 16S metagenomics can identify bacterial zoonotic pathogens causing severe febrile illness in humans, including potential novel agents.


Sujet(s)
Fièvre , Métagénomique , ARN ribosomique 16S , Humains , Tanzanie/épidémiologie , Adulte , Enfant d'âge préscolaire , Adolescent , Métagénomique/méthodes , Fièvre/microbiologie , Mâle , Femelle , Animaux , Enfant , ARN ribosomique 16S/génétique , Jeune adulte , Bactéries/génétique , Bactéries/classification , Bactéries/isolement et purification , Zoonoses bactériennes/microbiologie , Zoonoses bactériennes/épidémiologie , Infections bactériennes/microbiologie , Infections bactériennes/épidémiologie , Infections bactériennes/diagnostic , Zoonoses/microbiologie , Zoonoses/épidémiologie
7.
bioRxiv ; 2024 Jun 29.
Article de Anglais | MEDLINE | ID: mdl-38979270

RÉSUMÉ

TDP-43 proteinopathy, initially disclosed in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coexists with tauopathy in a variety of neurodegenerative disorders, termed multiple etiology dementias (MEDs), including Alzheimer's Disease (AD). While such co-pathology of TDP-43 is strongly associated with worsened neurodegeneration and steeper cognitive decline, the pathogenic mechanism underlying the exacerbated neuron loss remains elusive. The loss of TDP-43 splicing repression that occurs in presymptomatic ALS-FTD individuals suggests that such early loss could facilitate the pathological conversion of tau to accelerate neuron loss. Here, we report that the loss of TDP-43 repression of cryptic exons in forebrain neurons (CaMKII-CreER;Tardbp f/f mice) is necessary to exacerbate tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-dependent cleavage of endogenous tau to promote tauopathy. Corroborating this finding within the human context, we demonstrate that loss of TDP-43 function in iPSC-derived cortical neurons promotes early cryptic exon inclusion and subsequent caspase 3-mediated endoproteolysis of tau. Using a genetic approach to seed tauopathy in CaMKII-CreER;Tardbp f/f mice by expressing a four-repeat microtubule binding domain of human tau, we show that the amount of tau seed positively correlates with levels of caspase 3-cleaved tau. Importantly, we found that the vulnerability of hippocampal neurons to TDP-43 depletion is dependent on the amount of caspase 3-cleaved tau: from most vulnerable neurons in the CA2/3, followed by those in the dentate gyrus, to the least in CA1. Taken together, our findings strongly support the view that TDP-43 loss-of-function exacerbates tauopathy-dependent brain atrophy by increasing the sensitivity of vulnerable neurons to caspase 3-mediated endoproteolysis of tau, resulting in a greater degree of neurodegeneration in human disorders with co-pathologies of tau and TDP-43. Our work thus discloses novel mechanistic insights and therapeutic targets for human tauopathies harboring co-pathology of TDP-43 and provides a new MED model for testing therapeutic strategies.

8.
Cancer Cell ; 42(8): 1352-1369.e13, 2024 Aug 12.
Article de Anglais | MEDLINE | ID: mdl-39029464

RÉSUMÉ

Small cell lung cancers (SCLCs) are composed of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLCs, ∼12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes as top dependencies specific to POU2F3-positive SCLC. Notably, chemical disruption of mSWI/SNF ATPase activity attenuates proliferation of all POU2F3-positive SCLCs, while disruption of non-canonical BAF (ncBAF) via BRD9 degradation is effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF targets to and maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, clinical-grade pharmacologic disruption of SMARCA4/2 ATPases and BRD9 decreases POU2F3-SCLC tumor growth and increases survival in vivo. These results demonstrate mSWI/SNF-mediated governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for POU2F3-positive SCLCs.


Sujet(s)
Régulation de l'expression des gènes tumoraux , Tumeurs du poumon , Carcinome pulmonaire à petites cellules , Facteurs de transcription , Humains , Carcinome pulmonaire à petites cellules/génétique , Carcinome pulmonaire à petites cellules/métabolisme , Carcinome pulmonaire à petites cellules/anatomopathologie , Carcinome pulmonaire à petites cellules/traitement médicamenteux , Tumeurs du poumon/génétique , Tumeurs du poumon/métabolisme , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/traitement médicamenteux , Animaux , Facteurs de transcription/métabolisme , Facteurs de transcription/génétique , Souris , Lignée cellulaire tumorale , Prolifération cellulaire , Protéines chromosomiques nonhistones/métabolisme , Protéines chromosomiques nonhistones/génétique , Facteur de transcription Oct-3/métabolisme , Facteur de transcription Oct-3/génétique
9.
Cureus ; 16(6): e62636, 2024 Jun.
Article de Anglais | MEDLINE | ID: mdl-39036146

RÉSUMÉ

Introduction Tranexamic acid (TXA) administration perioperatively has demonstrated efficacy in reducing postoperative drops in hemoglobin levels and the need for transfusions among patients with peritrochanteric hip fractures. This study aims to perform a retrospective analysis to assess the impact on hemoglobin levels by comparing patients with fragility hip fractures who received TXA in the ED, in addition to the standard perioperative TXA dose, with those who did not receive TXA in the ED. Methods This study retrospectively reviewed 64 patient records from May 2020 to May 2021 at a Level II trauma center that were classified into two groups: patients who received one gram (g) of TXA in the ED, within five hours of injury (new protocol), or patients who received no TXA in the ED (old protocol). The primary outcomes of the study were hemoglobin and adverse events. An independent t-test was performed on continuous variables. A chi-square test was used to analyze noncontinuous variables. Statistical Product and Service Solutions (SPSS, version 25; IBM SPSS Statistics for Windows, Armonk, NY) was used for analysis. Statistical significance was set at a p value < 0.05. Results We measured the difference between hemoglobin on the day of surgery or day zero and on arrival in the ED, which was not statistically significant between the two protocols (p value = 0.322). The difference between hemoglobin levels on postoperative day one and on arrival in the ED was also not statistically significant (p = 0.339). Adverse events were lower in the new protocol but not statistically significant between the two protocols (p = 0.178). Conclusion Our study showed improved outcomes in postoperative hemoglobin with early administration of TXA in the ED. This is demonstrated by continuous higher postoperative hemoglobin in the new protocol group without an increase in adverse events. While the data did not achieve statistical significance, we believe there is clinical benefit in the early administration of TXA in the ED, a finding that continues to be explored and supported in the literature.

10.
Cureus ; 16(5): e61157, 2024 May.
Article de Anglais | MEDLINE | ID: mdl-38933616

RÉSUMÉ

Introduction Cardiac rehabilitation (CR) is an underutilized resource in patients with ischemic heart disease, despite being a Class IA recommendation. In this study, a multidisciplinary quality improvement (QI) team aimed to improve CR referrals by standardizing the ordering process at our hospital system. Method By using a collaborative approach involving the electronic medical record (EMR), medical provider education, and hospital protocols, our two-hospital healthcare system was able to successfully identify barriers to CR referral rates and implement interventions for these barriers. All physicians and medical providers, including ancillary staff, were educated on the EMR order sets to improve compliance by using automated order sets in the EMR. The CR referral order in the EMR included a statement regarding the application of evidence-based medicine, and a computerized provider order entry was included as a reminder to the ordering provider. The use of EMR was monitored monthly by the QI committee. Chi-square test and odds ratios were obtained for statistical analysis. Results Through provider-EMR education and patient education on discharge, CR referral rates significantly improved from 51.2 to 87.1% (p = 0.0001) in a 12-month period. The study included 1,499 patients in total. The improvement was statistically significant regardless of patient gender, race, or insurance coverage. Additionally, subgroup analysis in this study found that prior to standardization of the ordering process, African American patients were significantly less likely to be referred to CR compared to Caucasian patients. (51.2% vs. 41.0%, p=0.01). There was no statistically significant difference in the likelihood of CR referral between Caucasian and African American patients following the intervention (84.0% vs. 78.0%, p = 0.166). Conclusion This study shows that CR is an underutilized resource and that effective QI initiatives may not only increase CR referral rates but also close the gap between racial inequities in referral rates. Future research with multi-center randomized control trials is needed to further enhance its external generalizability to other institutions.

11.
Biophys J ; 123(16): 2443-2454, 2024 Aug 20.
Article de Anglais | MEDLINE | ID: mdl-38872310

RÉSUMÉ

Cells intricately sense mechanical forces from their surroundings, driving biophysical and biochemical activities. This mechanosensing phenomenon occurs at the cell-matrix interface, where mechanical forces resulting from cellular motion, such as migration or matrix stretching, are exchanged through surface receptors, primarily integrins, and their corresponding matrix ligands. A pivotal player in this interaction is the α5ß1 integrin and fibronectin (FN) bond, known for its role in establishing cell adhesion sites for migration. However, upregulation of the α5ß1-FN bond is associated with uncontrolled cell metastasis. This bond operates through catch bond dynamics, wherein the bond lifetime paradoxically increases with greater force. The mechanism sustaining the characteristic catch bond dynamics of α5ß1-FN remains unclear. Leveraging molecular dynamics simulations, our approach unveils a pivot-clip mechanism. Two key binding sites on FN, namely the synergy site and the RGD (Arg-Gly-Asp) motif, act as active points for structural changes in α5ß1 integrin. Conformational adaptations at these sites are induced by a series of hydrogen bond formations and breaks at the synergy site. We disrupt these adaptations through a double mutation on FN, known to reduce cell adhesion. A whole-cell finite-element model is employed to elucidate how the synergy site may promote dynamic α5ß1-FN binding, resisting cell contraction. In summary, our study integrates molecular- and cellular-level modeling to propose that FN's synergy site reinforces cell adhesion through enhanced binding dynamics and a mechanosensitive pivot-clip mechanism. This work sheds light on the interplay between mechanical forces and cell-matrix interactions, contributing to our understanding of cellular behaviors in physiological and pathological contexts.


Sujet(s)
Adhérence cellulaire , Fibronectines , Intégrine alpha5bêta1 , Mécanotransduction cellulaire , Simulation de dynamique moléculaire , Intégrine alpha5bêta1/métabolisme , Fibronectines/métabolisme , Fibronectines/composition chimique , Sites de fixation , Humains , Liaison aux protéines , Oligopeptides
12.
medRxiv ; 2024 May 04.
Article de Anglais | MEDLINE | ID: mdl-38746318

RÉSUMÉ

Molecular studies of Alzheimer's disease (AD) implicate potential links between autoimmunity and AD, but the underlying clinical relationships between these conditions remain poorly understood. Electronic health records (EHRs) provide an opportunity to determine the clinical risk relationship between autoimmune disorders and AD and understand whether specific disorders and disorder subtypes affect AD risk at the phenotypic level in human populations. We evaluated relationships between 26 autoimmune disorders and AD across retrospective observational case-control and cohort study designs in the EHR systems at UCSF and Stanford. We quantified overall and sex-specific AD risk effects that these autoimmune disorders confer. We identified significantly increased AD risk in autoimmune disorder patients in both study designs at UCSF and at Stanford. This pattern was driven by specific autoimmunity subtypes including endocrine, gastrointestinal, dermatologic, and musculoskeletal disorders. We also observed increased AD risk from autoimmunity in both women and men, but women with autoimmune disorders continued to have a higher AD prevalence than men, indicating persistent sex-specificity. This study identifies autoimmune disorders as strong risk factors for AD that validate across several study designs and EHR databases. It sets the foundation for exploring how underlying autoimmune mechanisms increase AD risk and contribute to AD pathogenesis.

13.
Sex Health ; 212024 May.
Article de Anglais | MEDLINE | ID: mdl-38801749

RÉSUMÉ

Background Launched in 2016 by Prevention Access Campaign, the 'Undetectable=Untransmittable' (U=U) campaign empowers people living with HIV to live full social, sexual and reproductive lives, dismantle stigma, promote increased treatment access, and advocate for updated HIV guidelines. Methods Key priorities for promoting improvements to community-centred, evidence-informed U=U policy and research were the focus of a half-day global roundtable held in 2023 alongside the 12th International AIDS Society Conference in Brisbane, Australia. After a series of presentations, experts in U=U research, policymaking, advocacy and HIV clinical care participated in facilitated discussions, and detailed notes were taken on issues related to advancing U=U policy and research. Results Expert participants shared that knowledge and trust in U=U remains uneven, and is largely concentrated among people living with HIV, particularly those connected to gay and bisexual networks. It was agreed that there is a need to ensure all members of priority populations are explicitly included in U=U policies that promote U=U. Participants also identified a need for policymakers, healthcare professionals, advocates and researchers to work closely with community-based organisations to ensure the U=U message is relevant, useful, and utilised in the HIV response. Adopting language, such as 'zero risk', was identified as crucial when describing undetectable viral load as an effective HIV prevention strategy. Conclusion U=U can have significant benefits for the mental and physical wellbeing of people living with HIV. There is an urgent need to address the structural barriers to HIV care and treatment access to ensure the full benefits of U=U are realised.


Sujet(s)
Infections à VIH , Politique de santé , Humains , Infections à VIH/prévention et contrôle , Santé mondiale , Stigmate social , Priorités en santé , Accessibilité des services de santé
14.
J Vet Pharmacol Ther ; 47(4): 252-256, 2024 Jul.
Article de Anglais | MEDLINE | ID: mdl-38557931

RÉSUMÉ

Lameness is a significant welfare concern in goats. Amphotericin B is used via intraarticular (IA) administration in models to study experimentally induced lameness in large animals. The main objective of this study was to estimate plasma pharmacokinetic (PK) parameters for amphotericin B in goats after a single IA administration. Liposomal amphotericin B was administered to ten Kiko-cross goats at a dose of 10 mg total (range: 0.34-0.51 mg/kg) via IA administration into the right hind lateral distal interphalangeal joint. Plasma samples were collected over 96 h. Amphotericin B concentrations were measured via liquid chromatography/mass spectrometry (LC-MS/MS). A non-compartmental analysis was used to derive PK parameters. Following single IA administration, maximum plasma concentration was estimated at 54.6 ± 16.5 ng/mL, and time to maximum concentration ranged from 6 to 12 h. Elimination half-life was estimated at 30.9 ± 16.5 h, and mean residence time was 45.1 ± 10.4 h. The volume of distribution after IA administration was 13.3 ± 9.4 L/kg. The area under the curve was 1481 ± 761 h*ng/mL. The achieved maximum concentration was less than the observed concentrations for other species and routes of administration. Further research is needed into the pharmacodynamics of IA liposomal amphotericin B in goats to determine specific research strategies.


Sujet(s)
Amphotéricine B , Aire sous la courbe , Capra , Animaux , Capra/métabolisme , Amphotéricine B/pharmacocinétique , Amphotéricine B/administration et posologie , Amphotéricine B/sang , Période , Injections articulaires/médecine vétérinaire , Mâle , Femelle , Antifongiques/pharmacocinétique , Antifongiques/administration et posologie , Antifongiques/sang
15.
Pediatrics ; 153(5)2024 May 01.
Article de Anglais | MEDLINE | ID: mdl-38646685

RÉSUMÉ

CONTEXT: Acute sinusitis is one of the leading causes of antibiotic prescriptions in children. No recent systematic reviews have examined the efficacy of antibiotics compared with placebo. OBJECTIVE: We sought to determine if antibiotics are superior to placebo in the treatment of acute sinusitis in children. DATA SOURCES: Medline and Embase were searched from their origin to July 2023. STUDY SELECTION: We considered randomized placebo-controlled studies focusing on the treatment of acute sinusitis. In all studies, symptoms were present for <4 weeks and subjects were <18 years of age. DATA EXTRACTION: Two authors independently extracted the data. We pooled data primarily using fixed-effects models. RESULTS: Analysis of 6 included studies showed that antibiotic treatment reduced the rate of treatment failure by 41% (with a risk ratio of 0.59; 95% confidence interval 0.49-0.72) compared with placebo. There was substantial heterogeneity between the studies (I2 = 69.7%), which decreased substantially when the 1 study with a high risk of bias was removed (I2 = 26.9%). Children treated with antibiotics were 1.6 times more likely to have diarrhea than those who were not treated with antibiotics (risk ratio = 1.62, 95% confidence interval 1.04-2.51). LIMITATIONS: A small number of studies were eligible for inclusion. Included studies differed in their methodology. CONCLUSIONS: In children with clinically diagnosed acute sinusitis, antibiotics significantly reduced the rate of treatment failure compared with placebo. However, given the favorable natural history of sinusitis, our results could also support close observation without immediate antibiotic treatment.


Sujet(s)
Antibactériens , Sinusite , Humains , Antibactériens/usage thérapeutique , Sinusite/traitement médicamenteux , Enfant , Maladie aigüe , Essais contrôlés randomisés comme sujet , Échec thérapeutique , Adolescent
16.
bioRxiv ; 2024 Mar 30.
Article de Anglais | MEDLINE | ID: mdl-38585725

RÉSUMÉ

Nuclear clearance and cytoplasmic aggregation of TDP-43 in neurons, initially identified in ALS-FTD, are hallmark pathological features observed across a spectrum of neurodegenerative diseases. We previously found that TDP-43 loss-of-function leads to the transcriptome-wide inclusion of deleterious cryptic exons in brains and biofluids post-mortem as well as during the presymptomatic stage of ALS-FTD, but upstream mechanisms that lead to TDP-43 dysregulation remain unclear. Here, we developed a web-based resource (SnapMine) to determine the levels of TDP-43 cryptic exon inclusion across hundreds of thousands of publicly available RNA sequencing datasets. We established cryptic exon inclusion across a variety of human cells and tissues to provide ground truth references for future studies on TDP-43 dysregulation. We then explored studies that were entirely unrelated to TDP-43 or neurodegeneration and found that ciclopirox olamine (CPX), an FDA-approved antifungal, can trigger the inclusion of TDP-43-associated cryptic exons in a variety of mouse and human primary cells. CPX induction of cryptic exon occurs via heavy metal toxicity and oxidative stress, suggesting that similar vulnerabilities could play a role in neurodegeneration. Our work demonstrates how diverse datasets can be linked through common biological features and underscores that public archives of sequencing data represent a vastly underutilized resource with tremendous potential for uncovering novel insights into complex biological mechanisms and diseases.

17.
Cureus ; 16(2): e54835, 2024 Feb.
Article de Anglais | MEDLINE | ID: mdl-38533141

RÉSUMÉ

Tourniquets have long been used in total knee arthroplasty due to the theoretical improvement of bleeding control, integration of cement-bone interface, visibility, and efficiency of the overall surgery. However, this has become increasingly disputed. Comparative studies in total knee arthroplasty employing chemical prophylaxis, i.e., tranexamic acid, have been conducted. This retrospective cohort study evaluated the effect of tranexamic with or without a tourniquet on mean blood loss, hemoglobin, and length of stay in total knee arthroplasty patients. A total of 153 patients' records met the inclusion criteria, 95 patients (62%) were in the tranexamic acid-only group while 58 patients (38%) were in the tranexamic acid plus tourniquet group. Based on mean blood loss in mL (827.5 without vs. 810.1 with the tourniquet, p=0.805), hemoglobin counts in g/dL (12.6 without vs. 12.5 with the tourniquet, p=0.598), and length of stay in days (1.0 days without vs. 1.1 with the tourniquet, p=0.204), there was no statistical difference between the tranexamic alone vs. tranexamic plus tourniquet groups. There were no statistical differences in the mean BMI between groups (32.3 without vs. 32.4 with tourniquets, p=0.901). The patient population had more women (64.1%) than men (35.9%) (p=0.001), but no significant difference in gender based on tourniquet use (p=0.521). The tourniquet group averaged three years younger than the tranexamic alone group (age mean 68.2 without vs 65.3 with tranexamic, p=0.029). This study found no identifiable difference in the three observed variables, indicating that tourniquet provides limited to no additional benefit in reducing blood loss over tranexamic alone in total knee arthroplasty, while tranexamic alone has no deleterious decrease in mean hemoglobin or increase in length of stay.

18.
Tissue Eng Part A ; 2024 Mar 14.
Article de Anglais | MEDLINE | ID: mdl-38323585

RÉSUMÉ

Tissue engineering strategies show great potential for repairing osteochondral defects in osteoarthritic joints; however, these approaches often rely on passaging cells multiple times to obtain enough cells to produce functional tissue. Unfortunately, monolayer expansion culture causes chondrocyte dedifferentiation, which is accompanied by a phenotypical and morphological shift in chondrocyte properties that leads to a reduction in the quality of de novo cartilage produced. Thus, the objective of this study was to evaluate transcriptional variations during in vitro expansion culture and determine how differences in cell phenotype from monolayer expansion alter development of functional engineered cartilage. We used an unbiased approach to explore genome-wide transcriptional differences in chondrocyte phenotype at passage 1 (P1), P3, and P5, and then seeded cells into hydrogel scaffolds at P3 and P5 to assess cells' abilities to produce cartilaginous extracellular matrix in three dimensional (3D). We identified distinct phenotypic differences, specifically for genes related to extracellular organization and cartilage development. Both P3 and P5 chondrocytes were able to produce chondrogenic tissue in 3D, with P3 cells producing matrix with greater compressive properties and P5 cells secreting matrix with higher glycosaminoglycan/DNA and collagen/DNA ratios. Furthermore, we identified 24 genes that were differentially expressed with passaging and enriched in human osteoarthritis (OA) genome-wide association studies, thereby prioritizing them as functionally relevant targets to improve protocols that recapitulate functional healthy cartilage with cells from adult donors. Specifically, we identified novel genes, such as TMEM190 and RAB11FIP4, which were enriched with human hip OA and may play a role in chondrocyte dedifferentiation. This work lays the foundation for several pathways and genes that could be modulated to enhance the efficacy for chondrocyte culture for tissue regeneration, which could have transformative impacts for cell-based cartilage repair strategies.

19.
J Biomech ; 165: 111964, 2024 Mar.
Article de Anglais | MEDLINE | ID: mdl-38412621

RÉSUMÉ

Lower back pain continues to be a global epidemic, limiting quality of life and ability to work, due in large part to symptomatic disc degeneration. Development of more effective and less invasive biological strategies are needed to treat disc degeneration. In vitro models such as macro- or micro-bioreactors or mechanically active organ-chips hold great promise in reducing the need for animal studies that may have limited clinical translatability, due to harsher and more complex mechanical loading environments in human discs than in most animal models. This review highlights the complex loading conditions of the disc in situ, evaluates state-of-the-art designs for applying such complex loads across multiple length scales, from macro-bioreactors that load whole discs to organ-chips that aim to replicate cellular or engineered tissue loading. Emphasis was placed on the rapidly evolving more customizable organ-chips, given their greater potential for studying the progression and treatment of symptomatic disc degeneration. Lastly, this review identifies new trends and challenges for using organ-chips to assess therapeutic strategies.


Sujet(s)
Dégénérescence de disque intervertébral , Disque intervertébral , Animaux , Humains , Qualité de vie , Techniques de culture d'organes , Bioréacteurs
20.
Nat Commun ; 15(1): 875, 2024 Jan 29.
Article de Anglais | MEDLINE | ID: mdl-38287010

RÉSUMÉ

RNA binding proteins (RBPs) are key regulators of RNA processing and cellular function. Technologies to discover RNA targets of RBPs such as TRIBE (targets of RNA binding proteins identified by editing) and STAMP (surveying targets by APOBEC1 mediated profiling) utilize fusions of RNA base-editors (rBEs) to RBPs to circumvent the limitations of immunoprecipitation (CLIP)-based methods that require enzymatic digestion and large amounts of input material. To broaden the repertoire of rBEs suitable for editing-based RBP-RNA interaction studies, we have devised experimental and computational assays in a framework called PRINTER (protein-RNA interaction-based triaging of enzymes that edit RNA) to assess over thirty A-to-I and C-to-U rBEs, allowing us to identify rBEs that expand the characterization of binding patterns for both sequence-specific and broad-binding RBPs. We also propose specific rBEs suitable for dual-RBP applications. We show that the choice between single or multiple rBEs to fuse with a given RBP or pair of RBPs hinges on the editing biases of the rBEs and the binding preferences of the RBPs themselves. We believe our study streamlines and enhances the selection of rBEs for the next generation of RBP-RNA target discovery.


Sujet(s)
Protéines de liaison à l'ARN , ARN , ARN/métabolisme , Sites de fixation/génétique , Protéines de liaison à l'ARN/métabolisme , Maturation post-transcriptionnelle des ARN
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