Psilocybin and chronic neuropathic pain: a systematic review.

BACKGROUND/IMPORTANCE: Chronic pain affects many people globally, requiring alternative management strategies. Psilocybin is gaining attention for its potential in chronic pain management despite being classified as Schedule I. OBJECTIVE: This systematic review critically evaluates the evidence for psilocybin, a Schedule I substance, in the treatment of chronic pain. The exact purpose of the review is to assess the impact of psilocybin on chronic pain relief, focusing on dosing protocols, treated conditions, and patient outcomes. EVIDENCE REVIEW: A comprehensive review of PubMed, CINAHL, Web of Science, Cochrane Library, and EMBASE was conducted up to January 2024. Eligibility criteria included studies evaluating psilocybin for chronic pain management. The risk of bias was assessed using the MASTER (MethodologicAl STandards for Epidemiological Research) scale, and the strength of evidence was graded using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). FINDINGS: The review identified 28 relevant studies focusing on dosing, treated conditions, and outcomes. The majority of the included studies (76.2%) were of low or very low quality. Several studies with moderate-to-low-quality evidence utilized a 0.14 mg/kg dosing protocol. The findings suggest promise for the use of psilocybin in chronic pain relief, though the quality of evidence is generally low. CONCLUSIONS: The current research shows potential for psilocybin as a treatment option for chronic pain relief. However, methodological issues and a lack of high-quality evidence underscore the need for further investigations with standardized protocols. Despite these limitations, the potential for psilocybin in chronic pain management is encouraging. PROSPERO REGISTRATION NUMBER: CRD42023493823.

Robust automated calcification meshing for personalized cardiovascular biomechanics.

Calcification has significant influence over cardiovascular diseases and interventions. Detailed characterization of calcification is thus desired for predictive modeling, but calcium deposits on cardiovascular structures are still often manually reconstructed for physics-driven simulations. This poses a major bottleneck for large-scale adoption of computational simulations for research or clinical use. To address this, we propose an end-to-end automated image-to-mesh algorithm that enables robust incorporation of patient-specific calcification onto a given cardiovascular tissue mesh. The algorithm provides a substantial speed-up from several hours of manual meshing to ~1 min of automated computation, and it solves an important problem that cannot be addressed with recent template-based meshing techniques. We validated our final calcified tissue meshes with extensive simulations, demonstrating our ability to accurately model patient-specific aortic stenosis and Transcatheter Aortic Valve Replacement. Our method may serve as an important tool for accelerating the development and usage of personalized cardiovascular biomechanics.

Amyloid precursor protein combinatorial phosphorylation code regulates AMPA receptor removal during distinct forms of synaptic plasticity.

Synaptic plasticity is essential for memory encoding and stabilization of neural network activity. Plasticity is impaired in neurodegenerative conditions including Alzheimer disease (AD). A central factor in AD is amyloid precursor protein (APP). Previous studies have suggested APP involvement in synaptic plasticity, but physiological roles of APP are not well understood. Here, we identified combinatorial phosphorylation sites within APP that regulate AMPA receptor trafficking during different forms of synaptic plasticity. Dual phosphorylation sites at threonine-668/serine-675 of APP promoted endocytosis of the GluA2 subunit of AMPA receptors during homeostatic synaptic plasticity. APP was also required for GluA2 internalization during NMDA receptor-dependent long-term depression, albeit via a distinct pair of phosphoresidues at serine-655/threonine-686. These data implicate APP as a central gate for AMPA receptor internalization during distinct forms of plasticity, unlocked by specific combinations of phosphoresidues, and suggest that APP may serve broad functions in learning and memory.

Literature Review: Mechanism, Indications, and Clinical Efficacy of Peripheral Nerve Stimulators in Lower Extremity Pain.

PURPOSE OF REVIEW: Lower extremity pain is deemed by Center for Disease Control and Prevention (CDC) to be a significant source of chronic pain in adults. If not appropriately managed, patients are subjected to risks of prolonged musculoskeletal dysfunction, disruption to quality of life, and elevated healthcare expenditures. Peripheral nerve stimulation (PNS) has shown great potential in recent years demonstrating efficacy in multiple diagnoses ranging from acute post-surgical pain to complex regional pain syndrome (CRPS). This study seeks to delineate efficacy of peripheral neuromodulation in the context of chronic lower extremity pain. RECENT FINDINGS: Prevailing clinical studies demonstrate evidence levels ranging from II to V (Oxford Centre of Level of Evidence) in lower limb PNS, attaining positive outcomes in pain scores, opioid use, and quality of life measures. Nerves most frequently targeted are the sciatic and femoral nerves with post-amputation pain and CRPS most commonly investigated for efficacy. PNS is a promising therapeutic modality demonstrated to be effective for a variety of nociceptive and neuropathic pain conditions in the lower extremity. PNS offers chronic pain physicians a powerful tool in the multi-modal management of lower limb chronic pain.

Race and Antibiotic Use for Children Hospitalized With Acute Respiratory Infections.

We sought to evaluate whether children hospitalized with acute respiratory infections experienced differences in antibiotic use by race and ethnicity. We found that likelihood of broad-spectrum antibiotic receipt differed across racial and ethnic groups. Future work should confirm this finding, evaluate causes, and ensure equitable antibiotic use.

Applications of Cryoneurolysis in Chronic Pain Management: a Review of the Current Literature.

PURPOSE OF REVIEW: The purpose of this review is to evaluate and summarize the literature investigating cryoneurolysis in the treatment of various chronic pain pathologies. RECENT FINDINGS: There is an increasing amount of interest in the use of cryoneurolysis in chronic pain, and various studies have investigated its use in lumbar facet joint pain, SI joint pain, post-thoracotomy syndrome, temporomandibular joint pain, chronic knee pain, phantom limb pain, neuropathic pain, and abdominal pain. Numerous retrospective studies and a more limited number of prospective, sham-controlled prospective studies suggest the efficacy of cryoneurolysis in managing these chronic pain pathologies with a low complication rate. However, more blinded, controlled, prospective studies comparing cryoneurolysis to other techniques are needed to clarify its relative risks and advantages.

Resveratrol differentially affects MMP-9 release from neurons and glia; implications for therapeutic efficacy.

Resveratrol, a naturally occurring polyphenol that activates sirtuin 1 (SIRT1), has been shown to reduce overall levels of matrix metalloprotease-9 (MMP-9) in cerebrospinal fluid (CSF) samples from patients with Alzheimer's dementia (AD). Depending on the site of release, however, MMP-9 has the potential to improve or impair cognition. In particular, its release from microglia or pericytes proximal to the blood brain barrier can damage the basement membrane, while neuronal activity-dependent release of this protease from glutamatergic neurons can instead promote dendritic spine expansion and long-term potentiation of synaptic plasticity. In the present study, we test the hypothesis that resveratrol reduces overall MMP-9 levels in CSF samples from patients with APOE4, an allele associated with increased glial inflammation. We also examine the possibility that resveratrol reduces inflammation-associated MMP release from cultured glia but spares neuronal activity-dependent release from cultured cortical neurons. We observe that resveratrol decreases overall levels of MMP-2 and MMP-9 in CSF samples from AD patients. Resveratrol also reduces CSF levels of tissue inhibitor of metalloproteinases-1 (TIMP-1), glial-derived protein that restricts long-term potentiation of synaptic transmission, in individuals homozygous for APOE4. Consistent with these results, we observe that resveratrol reduces basal and lipopolysaccharide (LPS)-stimulated MMP and TIMP-1 release from cultured microglia and astrocytes. In contrast, however, resveratrol does not inhibit release of MMP-9 from cortical neurons. Overall, these results are consistent with the possibility that while resveratrol reduces potentially maladaptive MMP and TIMP-1 release from activated glia, neuroplasticity-promoting MMP release from neurons is spared. In contrast, resveratrol reduces release of neurocan and brevican, extracellular matrix components that restrict neuroplasticity, from both neurons and glia. These data underscore the diversity of resveratrol's actions with respect to affected cell types and molecular targets and also suggest that further studies may be warranted to determine if its effects on glial MMP release could make it a useful adjunct for AD- and/or anti-amyloid therapy-related damage to the blood brain barrier.

Patient-Specific Heart Geometry Modeling for Solid Biomechanics Using Deep Learning.

Automated volumetric meshing of patient-specific heart geometry can help expedite various biomechanics studies, such as post-intervention stress estimation. Prior meshing techniques often neglect important modeling characteristics for successful downstream analyses, especially for thin structures like the valve leaflets. In this work, we present DeepCarve (Deep Cardiac Volumetric Mesh): a novel deformation-based deep learning method that automatically generates patient-specific volumetric meshes with high spatial accuracy and element quality. The main novelty in our method is the use of minimally sufficient surface mesh labels for precise spatial accuracy and the simultaneous optimization of isotropic and anisotropic deformation energies for volumetric mesh quality. Mesh generation takes only 0.13 seconds/scan during inference, and each mesh can be directly used for finite element analyses without any manual post-processing. Calcification meshes can also be subsequently incorporated for increased simulation accuracy. Numerous stent deployment simulations validate the viability of our approach for large-batch analyses. Our code is available at https://github.com/danpak94/Deep-Cardiac-Volumetric-Mesh.

Individualized Antibiotic Plans as a Quality Improvement Initiative to Reduce Carbapenem Use for Hematopoietic Cell Transplant Patients at a Freestanding Pediatric Hospital.

BACKGROUND: Providers must balance effective empiric therapy against toxicity risks and collateral damage when selecting antibiotic therapy for patients receiving hematopoietic cell transplant (HCT). Antimicrobial stewardship interventions during HCT are often challenging due to concern for undertreating potential infections. METHODS: In an effort to decrease unnecessary carbapenem exposure for patients undergoing HCT at our pediatric center, we implemented individualized antibiotic plans (IAPs) to provide recommendations for preengraftment neutropenia prophylaxis, empiric treatment of febrile neutropenia, and empiric treatment for hemodynamic instability. We compared monthly antibiotic days of therapy (DOT) adjusted per 1000 patient-days for carbapenems, antipseudomonal cephalosporins, and all antibiotics during two 3-year periods immediately before and after the implementation of IAPs to measure the impact of IAP on prescribing behavior. Bloodstream infection (BSIs) and Clostridioides difficile (CD) positivity test rates were also compared between cohorts. Last, providers were surveyed to assess their experience of using IAPs in antibiotic decision making. RESULTS: Overall antibiotic use decreased after the implementation of IAPs (monthly reduction of 19.6 DOT/1000 patient-days; P = .004), with carbapenems showing a continuing decline after IAP implementation. BSI and CD positivity rates were unchanged. More than 90% of providers found IAPs to be either extremely or very valuable for their practice. CONCLUSIONS: Implementation of IAPs in this high-risk HCT population led to reduction in overall antibiotic use without increase in rate of BSI or CD test positivity. The program was well received by providers.

Wherefore Art Tau? Functional importance of site-specific tau phosphorylation in diverse subcellular domains.

Tau has canonically been considered as an axonal protein, but studies have observed tau localization in other subcellular domains of neurons. This relocated tau has been identified in both physiological and pathological conditions, and it is often labeled mislocalized. Furthermore, these forms of tau are referred to as "hyperphosphorylated" without specifying the phosphosites involved. On the contrary, we speculate that tau may have multiple physiological functions in various locations regulated via specific phosphorylation sites, although this picture is obscured by a lack of comprehensive phosphosite analysis. Here, we examine findings in the literature on the subcellular location of tau and potential roles tau has in those regions. We intentionally focus on the site-specific phosphorylated patterns involved in governing these properties, which are not well elucidated. To facilitate understanding of these events, we have begun establishing a comprehensive map of tau phosphorylation signatures. Such efforts may clarify tau's diverse physiological functions beyond the axon as well as promote development of novel therapeutic strategies directed against distinct tau subpopulations.

Plk2 promotes synaptic destabilization through disruption of N-cadherin adhesion complexes during homeostatic adaptation to hyperexcitation.

Synaptogenesis in the brain is highly organized and orchestrated by synaptic cellular adhesion molecules (CAMs) such as N-cadherin and amyloid precursor protein (APP) that contribute to the stabilization and structure of synapses. Although N-cadherin plays an integral role in synapse formation and synaptic plasticity, its function in synapse dismantling is not as well understood. Synapse weakening and loss are prominent features of neurodegenerative diseases, and can also be observed during homeostatic compensation to neuronal hyperexcitation. Previously, we have shown that during homeostatic synaptic plasticity, APP is a target for cleavage triggered by phosphorylation by Polo-like kinase 2 (Plk2). Here, we found that Plk2 directly phosphorylates N-cadherin, and during neuronal hyperexcitation Plk2 promotes N-cadherin proteolytic processing, degradation, and disruption of complexes with APP. We further examined the molecular mechanisms underlying N-cadherin degradation. Loss of N-cadherin adhesive function destabilizes excitatory synapses and promotes their structural dismantling as a prerequisite to eventual synapse elimination. This pathway, which may normally help to homeostatically restrain excitability, could also shed light on the dysregulated synapse loss that occurs in cognitive disorders.

The human acetylcholinesterase C-terminal T30 peptide activates neuronal growth through alpha 7 nicotinic acetylcholine receptors and the mTOR pathway.

Acetylcholinesterase (AChE) is a highly conserved enzyme responsible for the regulation of acetylcholine signaling within the brain and periphery. AChE has also been shown to participate in non-enzymatic activity and contribute to cellular development and aging. In particular, enzymatic cleavage of the synaptic AChE isoform, AChE-T, is shown to generate a bioactive T30 peptide that binds to the ⍺7 nicotinic acetylcholine receptor (nAChR) at synapses. Here, we explore intracellular mechanisms of T30 signaling within the human cholinergic neural cell line SH-SY5Y using high performance liquid chromatography (HPLC) coupled to electrospray ionization mass spectrometry (ESI-MS/MS). Proteomic analysis of cells exposed to (100 nM) T30 for 3-days reveals significant changes within proteins important for cell growth. Specifically, bioinformatic analysis identifies proteins that converge onto the mammalian target of rapamycin (mTOR) pathway signaling. Functional experiments confirm that T30 regulates neural cell growth via mTOR signaling and ⍺7 nAChR activation. T30 was found promote mTORC1 pro-growth signaling through an increase in phosphorylated elF4E and S6K1, and a decrease in the autophagy LC3B-II protein. These findings are corroborated in hippocampal neurons and show that T30 promotes dendritic arborization. Taken together, our findings define mTOR as a novel pathway activated by T30 interaction with the nAChR and suggest a role for this process in human disease.

Needs-based novel digital curriculum for the neuromodulation training deficit: Pain Rounds.

This study reports the needs-based development, effectiveness and feasibility of a novel, comprehensive spinal cord stimulation (SCS) digital curriculum designed for pain medicine trainees. The curriculum aims to address the documented systematic variability in SCS education and empower physicians with SCS expertise, which has been linked to utilization patterns and patient outcomes. Following a needs assessment, the authors developed a three-part SCS e-learning video curriculum with baseline and postcourse knowledge tests. Best practices were used for educational video production and test-question development. The study period was from 1 February 2020 to 31 December 2020. A total of 202 US-based pain fellows across two cohorts (early-fellowship and late-fellowship) completed the baseline knowledge assessment, while 122, 96 and 88 participants completed all available post-tests for Part I (Fundamentals), Part II (Cadaver Lab) and Part III (Decision Making, The Literature and Critical Applications), respectively. Both cohorts significantly increased knowledge scores from baseline to immediate post-test in all curriculum parts (p<0.001). The early-fellowship cohort experienced a higher rate of knowledge gain for Parts I and II (p=0.045 and p=0.027, respectively). On average, participants viewed 6.4 out of 9.6 hours (67%) of video content. Self-reported prior SCS experience had low to moderate positive correlations with Part I and Part III pretest scores (r=0.25, p=0.006; r=0.37, p<0.001, respectively). Initial evidence suggests that Pain Rounds provides an innovative and effective solution to the SCS curriculum deficit. A future controlled study should examine this digital curriculum's long-term impact on SCS practice and treatment outcomes.

Food elimination diet is a viable alternative therapy for eosinophilic esophagitis responsive to proton pump inhibitors.

BACKGROUND: First-line treatment of eosinophilic esophagitis (EoE) includes monotherapy with proton-pump inhibitors (PPIs), food elimination diet (FED), or topical corticosteroids. Current guidelines suggest patients with EoE should continue any responsive first-line monotherapies. However, the efficacy of FED monotherapy in patients with EoE responsive to PPI monotherapy has not been well studied. Our study aimed to investigate how attempting FED monotherapy after experiencing remission of EoE after PPI monotherapy influenced long-term EoE management. METHODS: We retrospectively identified patients with EoE responsive to PPI monotherapy who trialed FED monotherapy. We then employed a mixed method approach to a prospective cohort. Selected patients were observed long term for quantitative outcomes, while qualitative results were obtained from patient surveys regarding their perspectives on the trial of FED monotherapy. RESULTS: We identified 22 patients who trialed FED monotherapy after experiencing remission of EoE following PPI monotherapy. Of these 22 patients, 13 had remission of EoE with FED monotherapy, while 9 had re-activation of EoE. Out of 22 patients, 15 were enrolled in a cohort for observation. No exacerbations of EoE occurred while on maintenance treatment. Most patients stated that they would recommend this process to others with EoE (93.33%) and that trial of FED monotherapy helped them identify a treatment plan that aligned with their lifestyle (80%). CONCLUSION: Our work shows that FED monotherapy can be an effective alternative for patients with EoE responsive to PPI monotherapy that may improve patient quality of life, suggesting alternative treatment options should be considered for monotherapy-responsive EoE.

Behcet disease: an undifferentiating and complex vasculitis.

Behçet Disease is a relapsing and remitting variable vessel vasculitis characterized by recurrent mucocutaneous ulcers that can involve almost every organ system in the body. Indeed, the presence of recurrent oral or genital ulcers with other auto-inflammatory symptoms should raise suspicion for this elusive disease. It is unique among the vasculitides in that it can affect vessels of small, medium, and large size and tends to involve venous rather than arterial circulation, and its effects on the pulmonary venous circulation are particularly notable for their role in disease mortality. Classically seen in Mediterranean, Middle-Eastern, and eastern Asian countries, and relatively rare in the United States, prevalence has been increasing, prompting an increased need for internists to be aware of Behcet's clinical presentation and treatment. As early recognition and diagnosis of the disease is key to successful treatment and better prognosis, this review provides a brief summary of the current etiological theories, important clinical manifestations, and treatments including newer biologic alternatives.

ACh Transfers: Homeostatic Plasticity of Cholinergic Synapses.

The field of homeostatic plasticity continues to advance rapidly, highlighting the importance of stabilizing neuronal activity within functional limits in the context of numerous fundamental processes such as development, learning, and memory. Most homeostatic plasticity studies have been focused on glutamatergic synapses, while the rules that govern homeostatic regulation of other synapse types are less understood. While cholinergic synapses have emerged as a critical component in the etiology of mammalian neurodegenerative disease mechanisms, relatively few studies have been conducted on the homeostatic plasticity of such synapses, particularly in the mammalian nervous system. An exploration of homeostatic mechanisms at the cholinergic synapse may illuminate potential therapeutic targets for disease management and treatment. We will review cholinergic homeostatic plasticity in the mammalian neuromuscular junction, the autonomic nervous system, central synapses, and in relation to pathological conditions including Alzheimer disease and DYT1 dystonia. This work provides a historical context for the field of cholinergic homeostatic regulation by examining common themes, unique features, and outstanding questions associated with these distinct cholinergic synapse types and aims to inform future research in the field.

The Impact of Smoking on the Development and Severity of Chronic Pain.

PURPOSE OF REVIEW: The purpose of this review is to examine the impact of smoking and its role on the development of chronic pain and provide a critical review of recent literature. RECENT FINDINGS: Recent studies demonstrate the bidirectional and dependent relationship between smoking and chronic pain. Those who are in pain have a more difficult time in the cessation of smoking as well as an increased sensitivity to pain during abstinence, lower confidence, and higher relapse rates. The fear of pain and the anxiety and depression that abstinence causes results in a grim outcome for long-term cessation. The dependent nature between chronic pain and smoking is affected by numerous variables. Providers should consider a multiprong approach to treating chronic pain and targeting smoking cessation treatment by providing motivational therapy, nicotine replacement, and medication therapies to prevent relapse, and providing those who are more likely to relapse with a higher level of care.

Quality of Life and Depressive Symptoms Among Peruvian University Students During the COVID-19 Pandemic.

Objective: To determine the factors associated with quality of life and depressive symptoms in Peruvian university students during the COVID-19 pandemic. Methods: Multicentre study in 1,634 students recruited by convenience sampling. The quality of life (QoL) was assessed with the European Quality of Life-5 Dimensions at three levels (EQ-5D-3L) and depressive symptoms with the Patient Health Questionnaire-9 (PHQ-9). To assess factors associated with QoL and depressive symptoms, linear regressions and fitted regressions were used, with robust coefficients of variance information (ß). Results: A 345 (21.1%) reported problems in performing daily activities, 544 (33.3%) reported pain and discomfort, 772 (47.2%) were moderately/very anxious or depressed. Furthermore, 207 (12.7%) had moderate-severe and severe depressive symptoms. Men reported better QoL than women (ß: 3.2; 95% CI: 1.1, 5.4; p = 0.004) and fewer depressive symptoms (ß: -0.7; 95% CI: -1.3, -0.2; p = 0.011). Ayacucho's residents had more depressive symptoms than Ancash's residents (ß: 0.8; 95% CI: 0.1, 1.5; p = 0.022) and Piura's residents had fewer depressive symptoms than Ancash's residents (ß: -1.195% CI: -1.8, -0.3, p = 0.005). Students who left home during quarantine reported more depressive symptoms (ß: 0.7, 95% CI: 0.2, 1.2, p = 0.006). Conclusion: Problems performing daily activities, pain and discomfort, as well as mild to severe depressive symptoms were found in more than three-quarters of the sample. Authorities could consider depression care to improve quality of life in regions where high rates of infection occurred during the pandemic.

Combination of Proton Pump Inhibitors and Food Elimination Diet for Eosinophilic Esophagitis Refractory to Monotherapy.

Background and Aims: Eosinophilic esophagitis (EoE) is an antigen-mediated inflammatory esophageal disease that is commonly treated with high-dose proton-pump inhibitors (PPIs), topical corticosteroids, or food elimination diet (FED) monotherapy. Combination treatment has not been well studied in the management of EoE. We aimed to determine if PPI and FED combination therapy was able to induce histologic remission in patients with EoE refractory to monotherapy. Methods: We conducted a retrospective cohort study identifying patients with EoE that was refractory to PPI monotherapy and FED monotherapy but histologically responsive to PPI and FED combination therapy. We also identified symptom changes through chart review. Results: Out of 405 EoE patients, 12 patients were identified with EoE that was refractory to PPI monotherapy and FED monotherapy but histologically responsive to PPI and FED combination therapy. Out of 12 patients, 11 (91.67%) noted resolution of symptoms while on combination therapy. Comparative analysis of peak eosinophil counts showed that patients achieved a median of 4.5 eos/hpf (interquartile range [IQR], 2-6.5), which was significantly decreased compared to baseline (median, 45; IQR, 35.5-50; Wilcoxon signed-rank test, P < .001), PPI monotherapy (median, 41; IQR, 26-50; Wilcoxon signed-rank test, P < .001), and FED monotherapy (median, 45; IQR, 17-67.5; Wilcoxon signed-rank test, P < .001). Conclusion: Our work shows that patients with EoE refractory to PPI monotherapy and FED monotherapy can successfully achieve histologic remission and symptom benefit with PPI and FED combination therapy. Therefore, combination therapy should be considered a viable option for patients with EoE who fail treatment with first-line monotherapies.