Integrated Feedforward and Feedback Mechanisms in Neurovascular Coupling.

Neurovascular coupling (NVC) is the mechanism that drives the neurovascular response to neural activation, and NVC dysfunction has been implicated in various neurologic diseases. NVC is driven by (1) nonmetabolic feedforward mechanisms that are mediated by various signaling pathways and (2) metabolic feedback mechanisms that involve metabolic factors. However, the interplay between these feedback and feedforward mechanisms remains unresolved. We propose that feedforward mechanisms normally drive a swift, neural activation-induced regional cerebral blood flow (rCBF) overshoot, which floods the tissue beds, leading to local hypocapnia and hyperoxia. The feedback mechanisms are triggered by the resultant hypocapnia (not hyperoxia), which causes cerebral vasoconstriction in the neurovascular unit that counterbalances the rCBF overshoot and returns rCBF to a level that matches the metabolic activity. If feedforward mechanisms function improperly (eg, in a disease state), the rCBF overshoot, tissue-bed flooding, and local hypocapnia fail to occur or occur on a smaller scale. Consequently, the neural activation-related increase in metabolic activity results in local hypercapnia and hypoxia, both of which drive cerebral vasodilation and increase rCBF. Thus, feedback mechanisms ensure the brain milieu's stability when feedforward mechanisms are impaired. Our proposal integrates the feedforward and feedback mechanisms underlying NVC and suggests that these 2 mechanisms work like a fail-safe system, to a certain degree. We also discussed the difference between NVC and cerebral metabolic rate-CBF coupling and the clinical implications of our proposed framework.

Using AI to Write a Review Article Examining the Role of the Nervous System on Skeletal Homeostasis and Fracture Healing.

PURPOSE OF REVIEW: Three review articles have been written that discuss the roles of the central and peripheral nervous systems in fracture healing. While content among the articles is overlapping, there is a key difference between them: the use of artificial intelligence (AI). In one paper, the first draft was written solely by humans. In the second paper, the first draft was written solely by AI using ChatGPT 4.0 (AI-only or AIO). In the third paper, the first draft was written using ChatGPT 4.0 but the literature references were supplied from the human-written paper (AI-assisted or AIA). This project was done to evaluate the capacity of AI to conduct scientific writing. Importantly, all manuscripts were fact checked and extensively edited by all co-authors rendering the final manuscript drafts significantly different from the first drafts. RECENT FINDINGS: Unsurprisingly, the use of AI decreased the time spent to write a review. The two AI-written reviews took less time to write than the human-written paper; however, the changes and editing required in all three manuscripts were extensive. The human-written paper was edited the most. On the other hand, the AI-only paper was the most inaccurate with inappropriate reference usage and the AI-assisted paper had the greatest incidence of plagiarism. These findings show that each style of writing presents its own unique set of challenges and advantages. While AI can theoretically write scientific reviews, from these findings, the extent of editing done subsequently, the inaccuracy of the claims it makes, and the plagiarism by AI are all factors to be considered and a primary reason why it may be several years into the future before AI can present itself as a viable alternative for traditional scientific writing.

Role of the Neurologic System in Fracture Healing: An Extensive Review.

PURPOSE OF REVIEW: Despite advances in orthopedics, there remains a need for therapeutics to hasten fracture healing. However, little focus is given to the role the nervous system plays in regulating fracture healing. This paucity of information has led to an incomplete understanding of fracture healing and has limited the development of fracture therapies that integrate the importance of the nervous system. This review seeks to illuminate the integral roles that the nervous system plays in fracture healing. RECENT FINDINGS: Preclinical studies explored several methodologies for ablating peripheral nerves to demonstrate ablation-induced deficits in fracture healing. Conversely, activation of peripheral nerves via the use of dorsal root ganglion electrical stimulation enhanced fracture healing via calcitonin gene related peptide (CGRP). Investigations into TLR-4, TrkB agonists, and nerve growth factor (NGF) expression provide valuable insights into molecular pathways influencing bone mesenchymal stem cells and fracture repair. Finally, there is continued research into the connections between pain and fracture healing with findings suggesting that anti-NGF may be able to block pain without affecting healing. This review underscores the critical roles of the central nervous system (CNS), peripheral nervous system (PNS), and autonomic nervous system (ANS) in fracture healing, emphasizing their influence on bone cells, neuropeptide release, and endochondral ossification. The use of TBI models contributes to understanding neural regulation, though the complex influence of TBI on fracture healing requires further exploration. The review concludes by addressing the neural connection to fracture pain. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.

Cracking the Code: The Role of Peripheral Nervous System Signaling in Fracture Repair.

PURPOSE OF REVIEW: The traditionally understated role of neural regulation in fracture healing is gaining prominence, as recent findings underscore the peripheral nervous system's critical contribution to bone repair. Indeed, it is becoming more evident that the nervous system modulates every stage of fracture healing, from the onset of inflammation to repair and eventual remodeling. RECENT FINDINGS: Essential to this process are neurotrophins and neuropeptides, such as substance P, calcitonin gene-related peptide, and neuropeptide Y. These molecules fulfill key roles in promoting osteogenesis, influencing inflammation, and mediating pain. The sympathetic nervous system also plays an important role in the healing process: while local sympathectomies may improve fracture healing, systemic sympathetic denervation impairs fracture healing. Furthermore, chronic activation of the sympathetic nervous system, often triggered by stress, is a potential impediment to effective fracture healing, marking an important area for further investigation. The potential to manipulate aspects of the nervous system offers promising therapeutic possibilities for improving outcomes in fracture healing. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.

Do Not Lose Your Nerve, Be Callus: Insights Into Neural Regulation of Fracture Healing.

PURPOSE OF REVIEW: Fractures are a prominent form of traumatic injury and shall continue to be for the foreseeable future. While the inflammatory response and the cells of the bone marrow microenvironment play significant roles in fracture healing, the nervous system is also an important player in regulating bone healing. RECENT FINDINGS: Considerable evidence demonstrates a role for nervous system regulation of fracture healing in a setting of traumatic injury to the brain. Although many of the impacts of the nervous system on fracture healing are positive, pain mediated by the nervous system can have detrimental effects on mobilization and quality of life. Understanding the role the nervous system plays in fracture healing is vital to understanding fracture healing as a whole and improving quality of life post-injury. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.

Characterization of age-associated inflammasome activation reveals tissue specific differences in transcriptional and post-translational inflammatory responses.

Aging is associated with systemic chronic, low-grade inflammation, termed 'inflammaging'. This pattern of inflammation is multifactorial and is driven by numerous inflammatory pathways, including the inflammasome. However, most studies to date have examined changes in the transcriptomes that are associated with aging and inflammaging, despite the fact that inflammasome activation is driven by a series of post-translational activation steps, culminating in the cleavage and activation of caspase-1. Here, we utilized transgenic mice expressing a caspase-1 biosensor to examine age-associated inflammasome activation in various organs and tissues to define these post-translational manifestations of inflammaging. Consistent with other studies, we observe increased inflammation, including inflammasome activation, in aged mice and specific tissues. However, we note that the degree of inflammasome activation is not uniformly associated with transcriptional changes commonly used as a surrogate for inflammasome activation in tissues. Furthermore, we used a skull thinning technique to monitor central nervous system inflammasome activation in vivo in aged mice and found that neuroinflammation is significantly amplified in aged mice in response to endotoxin challenge. Together, these data reveal that inflammaging is associated with both transcriptional and post-translational inflammatory pathways that are not uniform between tissues and establish new methodologies for measuring age-associated inflammasome activation in vivo and ex vivo.

Pain, Return to Community Status, and 90-Day Mortality Among Hospitalized Patients With Heart Failure.

BACKGROUND: Pain is common among patients with heart failure but has not been examined with short-term discharge outcomes. The purpose was to examine whether pain at discharge predicts return to community status and 90-day mortality among hospitalized patients with heart failure. METHODS: Data from medical records of 2169 patients hospitalized with heart failure were analyzed in this retrospective cohort study. The independent variable was a diagnosis of pain at discharge. Outcomes were return to community status (yes/no) and 90-day mortality. Logistic regression was used to address aims. Covariates included age, gender, race, vital signs, comorbid symptoms, comorbid conditions, cardiac devices, and length of stay. RESULTS: The sample had a mean age of 66.53 years, and was 57.4% women and 55.9% Black. Of 2169 patients, 1601 (73.8%) returned to community, and 117 (5.4%) died at or before 90 days. Patients with pain returned to community less frequently (69.6%) compared with patients without pain (75.2%), which was a statistically significant relationship (odds ratio, 0.74; 95% confidence interval, 0.57-0.97; P = .028). Other variables that predicted return to community status included age, comorbid conditions, dyspnea, fatigue, systolic blood pressure, and length of stay. Pain did not predict increased 90-day mortality. Variables that predicted mortality included age, liver disease, and systolic blood pressure. CONCLUSION: Patients with pain were less likely to return to community but did not have higher 90-day mortality. Pain in combination with other symptoms and comorbid conditions may play a role in mortality if acute pain versus chronic pain can be stratified in a future study.

High Diagnostic Yield and Clinical Utility of Next-Generation Sequencing in Children with Epilepsy and Neurodevelopmental Delays: A Retrospective Study.

Advances in genetics led to the identification of hundreds of epilepsy-related genes, some of which are treatable with etiology-specific interventions. However, the diagnostic yield of next-generation sequencing (NGS) in unexplained epilepsy is highly variable (10-50%). We sought to determine the diagnostic yield and clinical utility of NGS in children with unexplained epilepsy that is accompanied by neurodevelopmental delays and/or is medically intractable. A 5-year retrospective review was conducted at the American University of Beirut Medical Center to identify children who underwent whole exome sequencing (WES) or whole genome sequencing (WGS). Data on patient demographics, neurodevelopment, seizures, and treatments were collected. Forty-nine children underwent NGS with an overall diagnostic rate of 68.9% (27/38 for WES, and 4/7 for WGS). Most children (42) had neurodevelopmental delays with (18) or without (24) refractory epilepsy, and only three had refractory epilepsy without delays. The diagnostic yield was 77.8% in consanguineous families (18), and 61.5% in non-consanguineous families (26); consanguinity information was not available for one family. Genetic test results led to anti-seizure medication optimization or dietary therapies in six children, with subsequent improvements in seizure control and neurodevelopmental trajectories. Not only is the diagnostic rate of NGS high in children with unexplained epilepsy and neurodevelopmental delays, but also genetic testing in this population may often lead to potentially life-altering interventions.

Repeated closed-head mild traumatic brain injury-induced inflammation is associated with nociceptive sensitization.

BACKGROUND: Individuals who have experienced mild traumatic brain injuries (mTBIs) suffer from several comorbidities, including chronic pain. Despite extensive studies investigating the underlying mechanisms of mTBI-associated chronic pain, the role of inflammation in long-term pain after mTBIs is not fully elucidated. Given the shifting dynamics of inflammation, it is important to understand the spatial-longitudinal changes in inflammatory processes following mTBIs and their effects on TBI-related pain. METHODS: We utilized a recently developed transgenic caspase-1 luciferase reporter mouse model to monitor caspase-1 activation through a thinned skull window in the in vivo setting following three closed-head mTBI events. Organotypic coronal brain slice cultures and acutely dissociated dorsal root ganglion (DRG) cells provided tissue-relevant context of inflammation signal. Mechanical allodynia was assessed by mechanical withdrawal threshold to von Frey and thermal hyperalgesia withdrawal latency to radiant heat. Mouse grimace scale (MGS) was used to detect spontaneous or non-evoked pain. In some experiments, mice were prophylactically treated with MCC950, a potent small molecule inhibitor of NLRP3 inflammasome assembly to inhibit injury-induced inflammatory signaling. Bioluminescence spatiotemporal dynamics were quantified in the head and hind paws, and caspase-1 activation was confirmed by immunoblot. Immunofluorescence staining was used to monitor the progression of astrogliosis and microglial activation in ex vivo brain tissue following repetitive closed-head mTBIs. RESULTS: Mice with repetitive closed-head mTBIs exhibited significant increases of the bioluminescence signals within the brain and paws in vivo for at least one week after each injury. Consistently, immunoblotting and immunofluorescence experiments confirmed that mTBIs led to caspase-1 activation, astrogliosis, and microgliosis. Persistent changes in MGS and hind paw withdrawal thresholds, indicative of pain states, were observed post-injury in the same mTBI animals in vivo. We also observed enhanced inflammatory responses in ex vivo brain slice preparations and DRG for at least 3 days following mTBIs. In vivo treatment with MCC950 significantly reduced caspase-1 activation-associated bioluminescent signals in vivo and decreased stimulus-evoked and non-stimulus evoked nociception. CONCLUSIONS: Our findings suggest that the inflammatory states in the brain and peripheral nervous system following repeated mTBIs are coincidental with the development of nociceptive sensitization, and that these events can be significantly reduced by inhibition of NLRP3 inflammasome activation.

Dihydroceramides Derived from Bacteroidetes Species Sensitize TRPV1 Channels.

Bacterial colonization of open wounds is common, and patients with infected wounds often report significantly elevated pain sensitivity at the wound site. Transient Receptor Potential Vanilloid Type 1 (TRPV1) channels are known to play an important role in pain signaling and may be sensitized under pro-inflammatory conditions. Bacterial membrane components, such as phosphoethanolamine dihydroceramide (PEDHC), phosphoglycerol dihydroceramide (PGDHC), and lipopolysaccharide (LPS), are released in the environment from the Gram-negative bacteria of the Bacteroidetes species colonizing the infected wounds. Here, we used intracellular calcium imaging and patch-clamp electrophysiology approaches to determine whether bacterially derived PEDHC, PGDHC, or LPS can modulate the activity of the TRPV1 channels heterologously expressed in HEK cells. We found that PEDHC and PGDHC can sensitize TRPV1 in a concentration-dependent manner, whereas LPS treatment does not significantly affect TRPV1 activity in HEK cells. We propose that sensitization of TRPV1 channels by Bacteroidetes-derived dihydroceramides may at least in part underlie the increased pain sensitivity associated with wound infections.

Blocking receptor for advanced glycation end products (RAGE) or toll-like receptor 4 (TLR4) prevents posttraumatic epileptogenesis in mice.

OBJECTIVE: Effective treatment for the prevention of posttraumatic epilepsy is still not available. Here, we sought to determine whether blocking receptor for advanced glycation end products (RAGE) or toll-like receptor 4 (TLR4) signaling pathways would prevent posttraumatic epileptogenesis. METHODS: In a mouse undercut model of posttraumatic epilepsy, daily injections of saline, RAGE monoclonal antibody (mAb), or TAK242, a TLR4 inhibitor, were made for 1 week. Their effects on seizure susceptibility and spontaneous epileptic seizures were evaluated with a pentylenetetrazol (PTZ) test in 2 weeks and with continuous video and wireless electroencephalography (EEG) monitoring between 2 and 6 weeks after injury, respectively. Seizure susceptibility after undercut in RAGE knockout mice was also evaluated with the PTZ test. The lesioned cortex was analyzed with immunohistology. RESULTS: Undercut animals treated with RAGE mAb or TAK242 showed significantly higher seizure threshold than saline-treated undercut mice. Consistently, undercut injury in RAGE knockout mice did not cause a reduction in seizure threshold in the PTZ test. EEG and video recordings revealed a significant decrease in the cumulative spontaneous seizure events in the RAGE mAb- or TAK242-treated group (p < 0.001, when the RAGE mAb or TAK242 group is compared with the saline group). The lesioned cortical tissues of RAGE mAb- or TAK242-treated undercut group showed higher neuronal densities of Nissl staining and higher densities of glutamic acid decarboxylase 67-immunoreactive interneurons than the saline-treated undercut group. Immunostaining to GFAP and Iba-1 revealed lower densities of astrocytes and microglia in the cortex of the treatment groups, suggesting reduced glia activation. SIGNIFICANCE: RAGE and TLR4 signaling are critically involved in posttraumatic epileptogenesis. Blocking these pathways early after traumatic brain injury is a promising strategy for preventing posttraumatic epilepsy.

Imaging aortic valve calcification: significance, approach and implications.

Aortic stenosis is the most prevalent valvular heart disease worldwide, and rates are increasing with the growing and more elderly population. Although the precise mechanisms that underpin aortic valve stenosis are incompletely understood, pathological valvular calcification has emerged as a key instigator in mediating the biomechanical stiffening that can lead to symptoms, the need for aortic valve replacement, and death if left untreated. Here, we review the currently understood processes leading to aortic valve calcification, summarise the contemporary imaging assessments of valve calcification, and highlight how these might improve patient care and accelerate our pathological understanding and the development of an effective medical therapy.

Concentrations of HMGB1 and Hsp70 of healthy subjects in upper and lower airway: Literature Review and Meta-analysis.

Although high-mobility group box 1 and heat-shock protein 70 are implicated in airway diseases and suggested as relevant diagnostic biomarkers, their control concentrations in the airways have not yet been determined. This study aimed to evaluate concentration of healthy subjects for both these proteins in the upper and lower airways via meta-analysis. We searched MEDLINE, EMBASE, and Google Scholar for articles describing concentration of healthy subjects for these proteins. Data from healthy populations were combined using a random-effects model, and subgroup and sensitivity analyses were performed to determine between-study heterogeneity. We analyzed 22 studies involving 485 patients. Concentration of healthy subjects of high-mobility group box 1 and heat-shock protein 70 varied from "not detected" to 326.13 ng/mL and from 0.20 pg/mL to 9240.00 pg/mL, respectively, with the values showing significant heterogeneity. Subgroup analysis for high-mobility group box 1 revealed 13.63 ng/mL (95% CI 12.13-15.14), 100.31 ng/mL (95% CI -31.28-231.91), 9.54 ng/mL (95% CI 8.91-10.17), and 65.82 ng/mL (95% CI 55.51-76.14) for the lower airway, upper airway, pediatric populations, and adults, respectively, whereas that for heat-shock protein 70 revealed 20.58 pg/mL (95% CI 7.87-33.29) for the lower airway and 9240.00 ±11820 pg/mL for the upper airway. Although concentrations of healthy subjects of these proteins varied in the upper and lower airways, the levels of both these proteins were higher in the upper airway than in the lower airway, and these concentrations differed according to the age and sampling procedure. Our findings support the further evaluation of these proteins as biomarkers for airway-related diseases.

Post Procedural Peak Left Atrial Contraction Strain Predicts Recurrence of Arrhythmia after Catheter Ablation of Atrial Fibrillation.

BACKGROUND: Left atrial (LA) function can be impaired by the atrial fibrillation (AF) ablation and might be associated with the risk of recurrence. We sought to determine whether the post-procedural changes in LA function impact the risk of recurrence following AF ablation. METHODS: We retrospectively reviewed patients who underwent AF ablation between 2009 and 2011 and underwent transthoracic echocardiography before ablation, 1-day and 3-month after ablation. Peak left atrial contraction strain (PACS) and left atrial emptying fraction (LAEF) were evaluated during sinus rhythm and compared across the three time points. The primary endpoint was atrial tachyarrhythmia recurrence after ablation. RESULTS: A total of 144 patients were enrolled (mean age 61 ± 11 years, 77% male, 46% persistent AF). PACS and LAEF initially decreased 1-day following ablation but partially recovered within 3 months in PAF patients, with a similar trend in the PerAF patients. After median 24 months follow-up, 68 (47%) patients had recurrence. Patients with recurrence had higher PACS1-day than that in non-recurrence subjects (-10.9 ± 5.0% vs. -13.4 ± 4.7%, p = 0.003). PACS1-day -12% distinguished recurrence cases with a sensitivity of 67.7% and specificity of 60.5%. The Kaplan-Meier curves showed significant difference in 5-year cumulative probability of recurrence between those with PACS ≥ -12% and PACS < -12% (log rank p < 0.0001). Multivariate regression showed that PACS1-day was an independent risk factor of arrhythmia recurrence. CONCLUSIONS: Left atrial function deteriorates immediately following AF ablation and partially recovers in 3 months but remains abnormal in the majority of patients. PACS1-day post procedure predicts arrhythmia recurrence at long-term follow-up.

Small-molecule CaVα1⋠CaVß antagonist suppresses neuronal voltage-gated calcium-channel trafficking.

Extracellular calcium flow through neuronal voltage-gated CaV2.2 calcium channels converts action potential-encoded information to the release of pronociceptive neurotransmitters in the dorsal horn of the spinal cord, culminating in excitation of the postsynaptic central nociceptive neurons. The CaV2.2 channel is composed of a pore-forming α1 subunit (CaVα1) that is engaged in protein-protein interactions with auxiliary α2/δ and ß subunits. The high-affinity CaV2.2α1⋅CaVß3 protein-protein interaction is essential for proper trafficking of CaV2.2 channels to the plasma membrane. Here, structure-based computational screening led to small molecules that disrupt the CaV2.2α1⋅CaVß3 protein-protein interaction. The binding mode of these compounds reveals that three substituents closely mimic the side chains of hot-spot residues located on the α-helix of CaV2.2α1 Site-directed mutagenesis confirmed the critical nature of a salt-bridge interaction between the compounds and CaVß3 Arg-307. In cells, compounds decreased trafficking of CaV2.2 channels to the plasma membrane and modulated the functions of the channel. In a rodent neuropathic pain model, the compounds suppressed pain responses. Small-molecule α-helical mimetics targeting ion channel protein-protein interactions may represent a strategy for developing nonopioid analgesia and for treatment of other neurological disorders associated with calcium-channel trafficking.

Continuing professional development for veterinarians in a changing world.

The veterinary profession has time and again successfully adapted to new challenges and developments, with considerable evolution of the skills needed. Different contexts, production systems and societal requirements continue to shape the profession, resulting in an increasing demand for specialisation, interdisciplinary collaboration along value chains, and preparedness for the omnipresent risk of emerging diseases. To keep up with changes, new insights, advances in research and novel ways to address challenges, continuing professional development (CPD) and the adaptation and updating of the veterinary curriculum have been essential to maintain and enhance the quality and performance of Veterinary Services. This paper reviews actors involved in the provision of Veterinary Services and discusses how vital CPD is in addressing current and future challenges, by focusing on veterinarians and allied veterinary professionals. The authors examine how providers of CPD contribute to the system and how the internal and external factors of a cohort or individual affect the quality and impact of capacity development. The paper further examines the landscape of veterinary CPD in terms of organisational structures, pedagogical approaches, the transition from input- to outcome-based learning, modern delivery tools, and the demands on the different actors involved in the delivery of animal health services. The authors conclude that CPD is essential if the quality of Veterinary Services is to keep pace with the ever-increasing and evolving demands of the 21st century. A CPD programme should therefore be constructed in a way that is tailored to the needs of veterinary professionals and to the requirements of their workplace, whether they work with animal keepers, livestock value chains, national governments or international regulatory bodies. An optimised and successful veterinary sector requires an evidencebased CPD programme that keeps those professionals who are involved in the delivery of animal health services both competent and relevant in a changing world.

La profession vétérinaire s'est adaptée à maintes reprises et avec succès à de nouveaux défis et évolutions qui ont nécessité la mobilisation d'un grand nombre de compétences nouvelles. La diversité des contextes, des systèmes de production et des exigences sociétales impose à la profession vétérinaire des transformations continues, avec pour conséquences une demande croissante de spécialisation et de collaborations interdisciplinaires le long des chaînes de valeur et la nécessité de mieux se préparer au risque omniprésent de maladies émergentes. Face aux changements intervenus, aux nouvelles connaissances, aux progrès de la recherche et aux nouvelles manières de relever les défis, la formation professionnelle continue (FPC) et l'adaptation et actualisation des cursus d'enseignement vétérinaire ont joué un rôle déterminant pour maintenir et améliorer la qualité et les performances des Services vétérinaires. Les auteurs font le point sur les divers prestataires de services vétérinaires et examinent le rôle essentiel de la FPC pour relever les défis actuels et futurs, en mettant l'accent sur les vétérinaires et les professions connexes travaillant en lien avec les vétérinaires. Ils analysent la contribution des fournisseurs de FPC au système de santé animale, ainsi que l'influence sur la qualité et l'impact du renforcement des capacités d'un certain nombre de facteurs internes et externes à l'échelle des cohortes ou des individus. Les auteurs décrivent également le paysage de la FPC dans le domaine vétérinaire et plus particulièrement les structures organisationnelles, les approches pédagogiques, la transition d'un apprentissage axé sur les contenus à un apprentissage axé sur les résultats, les outils modernes de formation et les exigences imposées aux différents prestataires de services de santé animale dans un monde en constante évolution. En conclusion, les auteurs insistent sur l'importance cruciale de mettre en place des dispositifs de formation professionnelle continue destinés au secteur vétérinaire, afin que la qualité des services fournis soit à la hauteur des exigences croissantes et en constante évolution du 21e siècle. Les programmes de FPC doivent donc être conçus en veillant à s'adapter aux besoins des vétérinaires et des professionnels des domaines connexes concernant les compétences spécifiques qu'ils doivent déployer en fonction des exigences de leur activité, qu'ils travaillent auprès des gardiens d'animaux, des professionnels des filières issues de l'élevage, des gouvernements nationaux ou des organismes internationaux chargés de l'élaboration de normes. Un secteur vétérinaire optimisé et performant nécessite un programme de FPC fondé sur des données concrètes afin que les vétérinaires et les autres prestataires de services de santé animale puissent maintenir leur niveau de compétences ainsi que la pertinence de leurs interventions au regard des exigences évolutives d'un monde en pleine transformation. La profession vétérinaire s'est adaptée à maintes reprises et avec succès à de nouveaux défis et évolutions qui ont nécessité la mobilisation d'un grand nombre de compétences nouvelles. La diversité des contextes, des systèmes de production et des exigences sociétales impose à la profession vétérinaire des transformations continues, avec pour conséquences une demande croissante de spécialisation et de collaborations interdisciplinaires le long des chaînes de valeur et la nécessité de mieux se préparer au risque omniprésent de maladies émergentes. Face aux changements intervenus, aux nouvelles connaissances, aux progrès de la recherche et aux nouvelles manières de relever les défis, la formation professionnelle continue (FPC) et l'adaptation et actualisation des cursus d'enseignement vétérinaire ont joué un rôle déterminant pour maintenir et améliorer la qualité et les performances des Services vétérinaires. Les auteurs font le point sur les divers prestataires de services vétérinaires et examinent le rôle essentiel de la FPC pour relever les défis actuels et futurs, en mettant l'accent sur les vétérinaires et les professions connexes travaillant en lien avec les vétérinaires. Ils analysent la contribution des fournisseurs de FPC au système de santé animale, ainsi que l'influence sur la qualité et l'impact du renforcement des capacités d'un certain nombre de facteurs internes et externes à l'échelle des cohortes ou des individus. Les auteurs décrivent également le paysage de la FPC dans le domaine vétérinaire et plus particulièrement les structures organisationnelles, les approches pédagogiques, la transition d'un apprentissage axé sur les contenus à un apprentissage axé sur les résultats, les outils modernes de formation et les exigences imposées aux différents prestataires de services de santé animale dans un monde en constante évolution. En conclusion, les auteurs insistent sur l'importance cruciale de mettre en place des dispositifs de formation professionnelle continue destinés au secteur vétérinaire, afin que la qualité des services fournis soit à la hauteur des exigences croissantes et en constante évolution du 21e siècle. Les programmes de FPC doivent donc être conçus en veillant à s'adapter aux besoins des vétérinaires et des professionnels des domaines connexes concernant les compétences spécifiques qu'ils doivent déployer en fonction des exigences de leur activité, qu'ils travaillent auprès des gardiens d'animaux, des professionnels des filières issues de l'élevage, des gouvernements nationaux ou des organismes internationaux chargés de l'élaboration de normes. Un secteur vétérinaire optimisé et performant nécessite un programme de FPC fondé sur des données concrètes afin que les vétérinaires et les autres prestataires de services de santé animale puissent maintenir leur niveau de compétences ainsi que la pertinence de leurs interventions au regard des exigences évolutives d'un monde en pleine transformation. La profession vétérinaire s'est adaptée à maintes reprises et avec succès à de nouveaux défis et évolutions qui ont nécessité la mobilisation d'un grand nombre de compétences nouvelles. La diversité des contextes, des systèmes de production et des exigences sociétales impose à la profession vétérinaire des transformations continues, avec pour conséquences une demande croissante de spécialisation et de collaborations interdisciplinaires le long des chaînes de valeur et la nécessité de mieux se préparer au risque omniprésent de maladies émergentes. Face aux changements intervenus, aux nouvelles connaissances, aux progrès de la recherche et aux nouvelles manières de relever les défis, la formation professionnelle continue (FPC) et l'adaptation et actualisation des cursus d'enseignement vétérinaire ont joué un rôle déterminant pour maintenir et améliorer la qualité et les performances des Services vétérinaires. Les auteurs font le point sur les divers prestataires de services vétérinaires et examinent le rôle essentiel de la FPC pour relever les défis actuels et futurs, en mettant l'accent sur les vétérinaires et les professions connexes travaillant en lien avec les vétérinaires. Ils analysent la contribution des fournisseurs de FPC au système de santé animale, ainsi que l'influence sur la qualité et l'impact du renforcement des capacités d'un certain nombre de facteurs internes et externes à l'échelle des cohortes ou des individus. Les auteurs décrivent également le paysage de la FPC dans le domaine vétérinaire et plus particulièrement les structures organisationnelles, les approches pédagogiques, la transition d'un apprentissage axé sur les contenus à un apprentissage axé sur les résultats, les outils modernes de formation et les exigences imposées aux différents prestataires de services de santé animale dans un monde en constante évolution. En conclusion, les auteurs insistent sur l'importance cruciale de mettre en place des dispositifs de formation professionnelle continue destinés au secteur vétérinaire, afin que la qualité des services fournis soit à la hauteur des exigences croissantes et en constante évolution du 21e siècle. Les programmes de FPC doivent donc être conçus en veillant à s'adapter aux besoins des vétérinaires et des professionnels des domaines connexes concernant les compétences spécifiques qu'ils doivent déployer en fonction des exigences de leur activité, qu'ils travaillent auprès des gardiens d'animaux, des professionnels des filières issues de l'élevage, des gouvernements nationaux ou des organismes internationaux chargés de l'élaboration de normes. Un secteur vétérinaire optimisé et performant nécessite un programme de FPC fondé sur des données concrètes afin que les vétérinaires et les autres prestataires de services de santé animale puissent maintenir leur niveau de compétences ainsi que la pertinence de leurs interventions au regard des exigences évolutives d'un monde en pleine transformation.

La profesión veterinaria siempre ha sabido adaptarse con éxito a las novedades y nuevos problemas que han ido surgiendo, y que requieren la adquisición de nuevos conocimientos y aptitudes. Los diferentes contextos, sistemas productivos y necesidades sociales siguen configurando la profesión veterinaria y generando una creciente demanda de especialización, de colaboración interdisciplinar en todos los eslabones de las cadenas de valor y de preparación ante el omnipresente riesgo que plantean las enfermedades emergentes. El perfeccionamiento profesional continuo (PPC) y la adaptación y actualización de los planes de estudios veterinarios han sido factores esenciales para seguir el ritmo de las transformaciones, las nuevas ideas, los avances científicos y las novedosas respuestas a los problemas y, gracias a ello, mantener y mejorar la calidad y el desempeño de los Servicios Veterinarios. Los autores pasan revista a cuantos agentes intervienen en la prestación de servicios veterinarios y, centrándose en los veterinarios y cuerpos profesionales conexos, exponen la función crucial que cumple el PPC para hacer frente a los problemas de hoy y de mañana. También explican cómo contribuyen al sistema los proveedores de PPC y cómo los factores internos y externos de una cohorte o un individuo afectan a la calidad y la repercusión del desarrollo de capacidades. Además, describen el panorama que ofrece el PPC en veterinaria desde el punto de vista de las estructuras organizativas, los planteamientos pedagógicos, la transición del aprendizaje de asimilación al aprendizaje por resultados, las modernas herramientas de trabajo y las exigencias que deben satisfacer los distintos agentes que intervienen en la prestación de servicios zoosanitarios en un mundo en plena evolución. Los autores concluyen que es de la máxima importancia ocuparse del PPC para que los servicios veterinarios dispensados sigan siendo de calidad y respondiendo a las crecientes y mudables exigencias que trae consigo el siglo XXI. Hay que establecer pues un programa de PPC especialmente adaptado a las necesidades de los veterinarios y cuerpos profesionales conexos, pensando en dotarlos de las competencias necesarias para satisfacer los requisitos propios de su lugar de trabajo, ya obren al servicio de la producción animal, de cadenas de valor ganaderas, de administraciones nacionales o de organismos internacionales de reglamentación. Un sector veterinario optimizado y eficaz requiere un programa de PPC científicamente fundamentado, que sirva a los veterinarios y demás agentes de la prestación de servicios zoosanitarios para seguir siendo a la vez competentes y útiles ante las cambiantes exigencias que les plantea un mundo en plena evolución.

Assessment, Quantification, and Management of Fracture Pain: from Animals to the Clinic.

PURPOSE OF REVIEW: Fractures are painful and disabling injuries that can occur due to trauma, especially when compounded with pathologic conditions, such as osteoporosis in older adults. It is well documented that acute pain management plays an integral role in the treatment of orthopedic patients. There is no current therapy available to completely control post-fracture pain that does not interfere with bone healing or have major adverse effects. In this review, we focus on recent advances in the understanding of pain behaviors post-fracture. RECENT FINDINGS: We review animal models of bone fracture and the assays that have been developed to assess and quantify spontaneous and evoked pain behaviors, including the two most commonly used assays: dynamic weight bearing and von Frey testing to assess withdrawal from a cutaneous (hindpaw) stimulus. Additionally, we discuss the assessment and quantification of fracture pain in the clinical setting, including the use of numeric pain rating scales, satisfaction with pain relief, and other biopsychosocial factor measurements. We review how pain behaviors in animal models and clinical cases can change with the use of current pain management therapies. We conclude by discussing the use of pain behavioral analyses in assessing potential therapeutic treatment options for addressing acute and chronic fracture pain without compromising fracture healing. There currently is a lack of effective treatment options for fracture pain that reliably relieve pain without potentially interfering with bone healing. Continued development and verification of reliable measurements of fracture pain in both pre-clinical and clinical settings is an essential aspect of continued research into novel analgesic treatments for fracture pain.

Understanding further education as a context for public health intervention: qualitative findings from a study process evaluation.

BACKGROUND: Over 1.2 million 16-18 year-olds are enrolled in further education (FE-advanced secondary education) in England. Life course transitions provide opportunities to change, establish or reinforce health behaviours. FE presents an opportunity for public health improvement, yet few interventions target this setting. Using a smoking prevention intervention, we explore how young people were viewed in FE and how this affected intervention acceptability. METHODS: Eleven student and five staff focus groups were conducted in three intervention institutions (two colleges, one school sixth-form), as part of the process evaluation of a smoking prevention feasibility study. FE managers in intervention and control institutions were also interviewed (n = 5). Data were analysed using thematic analysis. RESULTS: In both colleges and the sixth-form, students were viewed as emergent adults and treated differently from 'school-children', in practice if not in policy. Colleges permitted smoking in designated areas; in the school sixth-form smoking was unofficially tolerated but concealed from younger students. Using staff to deliver anti-smoking messages reintroduced an unwanted power dynamic which disrupted perceptions of students as young adults. CONCLUSIONS: FE is an important setting for young people's health. Understanding the culture and context of FE is critical in designing acceptable and effective public health interventions.

The role of deficient pain modulatory systems in the development of persistent post-traumatic headaches following mild traumatic brain injury: an exploratory longitudinal study.

BACKGROUND: Post-traumatic headache (PTH) is one of the most common and long-lasting symptoms following mild traumatic brain injury (TBI). However, the pathological mechanisms underlying the development of persistent PTH remain poorly understood. The primary purpose of this prospective pilot study was to evaluate whether early pain modulatory profiles (sensitization and endogenous pain inhibitory capacity) and psychological factors after mild TBI predict the development of persistent PTH in mild TBI patients. METHODS: Adult mild TBI patients recruited from Level I Emergency Department Trauma Centers completed study sessions at 1-2 weeks, 1-month, and 4-months post mild TBI. Participants completed the following outcome measures during each session: conditioned pain modulation to measure endogenous pain inhibitory capacity, temporal summation of pain and pressure pain thresholds of the head to measure sensitization of the head, Pain Catastrophizing Scale, Center for Epidemiological Studies - Depression Scale, and a standardized headache survey. Participants were classified into persistent PTH (PPTH) and no-PPTH groups based on the 4-month data. RESULTS: The results revealed that mild TBI patients developing persistent PTH exhibited significantly diminished pain inhibitory capacity, and greater depression and pain catastrophizing following injury compared to those who do not develop persistent PTH. Furthermore, logistic regression indicated that headache pain intensity at 1-2 weeks and pain inhibitory capacity on the conditioned pain modulation test at 1-2 weeks predicted persistent PTH classification at 4 months post injury. CONCLUSIONS: Overall, the results suggested that persistent PTH is characterized by dysfunctional alterations in endogenous pain modulatory function and psychological processes in the early stages following mild TBI, which likely exacerbate risk for the maintenance of PTH.

High mobility group box 1 protein regulates osteoclastogenesis through direct actions on osteocytes and osteoclasts in vitro.

Old age and Cx43 deletion in osteocytes are associated with increased osteocyte apoptosis and osteoclastogenesis. We previously demonstrated that apoptotic osteocytes release elevated concentrations of the proinflammatory cytokine, high mobility group box 1 protein (HMGB1) and apoptotic osteocyte conditioned media (CM) promotes osteoclast differentiation. Further, prevention of osteocyte apoptosis blocks osteoclast differentiation and attenuates the extracellular release of HMGB1 and RANKL. Moreover, sequestration of HMGB1, in turn, reduces RANKL production/release by MLO-Y4 osteocytic cells silenced for Cx43 (Cx43def ), highlighting the possibility that HMGB1 promotes apoptotic osteocyte-induced osteoclastogenesis. However, the role of HMGB1 signaling in osteocytes has not been well studied. Further, the mechanisms underlying its release and the receptor(s) responsible for its actions is not clear. We now report that a neutralizing HMGB1 antibody reduces osteoclast formation in RANKL/M-CSF treated bone marrow cells. In bone marrow macrophages (BMMs), toll-like receptor 4 (TLR4) inhibition with LPS-RS, but not receptor for advanced glycation end products (RAGE) inhibition with Azeliragon attenuated osteoclast differentiation. Further, inhibition of RAGE but not of TLR4 in osteoclast precursors reduced osteoclast number, suggesting that HGMB1 produced by osteoclasts directly affects differentiation by activating TLR4 in BMMs and RAGE in preosteoclasts. Our findings also suggest that increased osteoclastogenesis induced by apoptotic osteocytes CM is not mediated through HMGB1/RAGE activation and that direct HMGB1 actions in osteocytes stimulate pro-osteoclastogenic signal release from Cx43def osteocytes. Based on these findings, we propose that HMGB1 exerts dual effects on osteoclasts, directly by inducing differentiation through TLR4 and RAGE activation and indirectly by increasing pro-osteoclastogenic cytokine secretion from osteocytes.