Search Results (52)

Botulinum toxin is a neurotoxin that is used in the treatments for several medical conditions, such as dystonia, spasticity, hemifacial spasm, overactive bladder, and hyperhidrosis. This toxin can potentially treat several pain disorders through botulinum toxin’s ability to inhibit the release of pro-nociceptive neurotransmitters into the synaptic cleft and its possible action on the central nervous system. This narrative review addresses the use of botulinum toxin in treating primary and secondary headaches and facial pain disorders. The highest level of evidence supporting its use varies among the headache and facial pain disorders: chronic migraine (multicenter, double-blind, placebo-controlled studies), trigeminal neuralgia (double-blind, placebo-controlled studies), post-traumatic headache (double-blind, placebo-controlled study), cluster headache (open-label clinical trials), nummular headache (open-label clinical trial), headache attributed to craniocervical dystonia (prospective cohort study), new daily persistent headache (retrospective cohort study), hemicrania continua, and SUNCT and SUNA (case reports). The site of toxin application and the doses used vary among the studies and depending on headache type. Botulinum toxin has been shown to be safe in different studies, with generally mild adverse reactions. Full article

Background/Objectives: The image guidance of choice for the combination therapy of radiofrequency ablation (RFA) and vertebral augmentation (VA) in the context of vertebral disease from spinal metastases are fluoroscopy and computer tomography (CT). Here, we aimed to assess the roles of both imaging modalities and if adoption of either would influence clinical outcomes of pain, physical function, and quality of life (QoL). RFA has been favored as a minimally invasive option for managing painful spinal metastases, and it is often coupled with VA to treat underlying osseous structural instability. This combination therapy of RFA with VA, which could be performed under CT or fluoroscopy, has in recent years been recognized as highly successful for pain control and functional restoration of metastatic spine lesions. Methods: Our scoping review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). The databases accessed were Medline and Embase, and the time frame of the search was set from database inception to 2 January 2025. The inclusion eligibility included primary research studies utilizing clearly defined imaging modalities of interest with measurable clinical end points of pain, quality of life (QoL), analgesic use, or complications. Results: Twenty-two articles were identified after screening fifty-eight papers using the databases. Fluoroscopy alone was the more frequently adopted imaging modality (n = 17/22, 77.3%). Almost all of the papers, regardless of the imaging modality used, consistently demonstrated reduction in pain, improvement in QoL, as well as a decrease in analgesia use. Complications were present but had minimal clinical implications, aside from a single article which appeared to demonstrate significantly higher cement leak rates with a singular case of resultant paraplegia. Conclusions: Fluoroscopy- and CT-guided RFA with VA have both proven to be efficacious in reducing patient discomfort and improving functionality while keeping risks of permanent neurological injuries to a minimum. Full article

In human–robot collaborative environments, predicting and explaining robotic grasp failures is crucial for effective operation. While machine learning models can predict failures accurately, they often lack transparency, limiting their utility in critical applications. This paper presents a comparative analysis of three post hoc explanation methods—Tree-SHAP, LIME, and TreeInterpreter—for explaining grasp failure predictions from white-box and black-box models. Using a simulated robotic grasping dataset, we evaluate these methods based on their agreement in identifying important features, similarity in feature importance rankings, dependency on model type, and computational efficiency. Our findings reveal that Tree-SHAP and TreeInterpreter demonstrate stronger consistency with each other than with LIME, particularly for correctly predicted failures. The choice of ML model significantly affects explanation consistency, with simpler models yielding more agreement across methods. TreeInterpreter offers a substantial computational advantage, operating approximately 24 times faster than Tree-SHAP and over 2000 times faster than LIME for complex models. All methods consistently identify effort in joint 1 across fingers 1 and 3 as critical factors in grasp failures, aligning with mechanical design principles. These insights contribute to developing more transparent and reliable robotic grasping systems, enabling better human–robot collaboration through improved failure understanding and prevention. Full article

Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest 5-year survival rates of all cancers, and limited treatment options exist. Immunotherapy is effective in some cancer types, but the immunosuppressive tumor microenvironment (TME) of PDAC is a barrier to effective immunotherapy. CXCR2+ myeloid-derived suppressor cells (MDSCs) are abundant in PDAC tumors in humans and in mouse models. MDSCs suppress effector cell function, making them attractive targets for restoring anti-tumor immunity. In this study, we show that the most abundant soluble factors released from a genetically diverse set of human and mouse PDAC cells are CXCR2 ligands, including CXCL8, CXCL5, and CXCL1. Expression of CXCR2 ligands is at least partially dependent on mutant KRAS and NFκB signaling, which are two of the most commonly dysregulated pathways in PDAC. We show that MDSCs are the most prevalent immune cells in PDAC tumors. MDSCs expressed high levels of CXCR2, and we found that myeloid cells readily migrate toward conditioned media (CM) prepared from PDAC cultures. We designed CXCR2 ligand-Fc fusion proteins to modulate the CXCR2 chemotactic signaling axis. Unexpectedly, these fusion proteins were superior to native chemokines in binding and activation of CXCR2 on myeloid cells. These “superkines” were potent inhibitors of PDAC CM-induced myeloid cell migration and were superior to CXCR2 small-molecule inhibitors and neutralizing antibodies. Our findings suggest that CXCR2 superkines may disrupt myeloid cell recruitment to PDAC tumors, ultimately improving immunotherapy outcomes in patients with PDAC. Full article

Background/Objectives: Celecoxib, a COX-2 selective nonsteroidal anti-inflammatory drug (NSAID), is widely prescribed for pain management due to its efficacy and improved gastrointestinal safety profile compared to traditional NSAIDs. Understanding prescription trends and their comparison to other NSAIDs provides valuable insight into prescribing behaviors in clinical settings. Methods: This retrospective study analyzed celecoxib prescriptions written by three pain management physicians in a single institution over a 16-month period from 1 January 2023 to 30 April 2024. Prescription data were collected and grouped into four 4-month intervals to assess temporal trends. Additionally, we compared celecoxib prescriptions to other commonly prescribed NSAIDs, including ibuprofen, meloxicam, naproxen, and diclofenac. Results: A total of 143 celecoxib prescriptions were identified during the study period, with a steady increase observed across consecutive intervals: 8 prescriptions from January–April 2023, 22 from May–August 2023, 46 from September–December 2023, and 67 from January–April 2024. In comparison, a total of 165 prescriptions were written for other NSAIDs over the same period, with 26 prescriptions from January–April 2023, 41 from May–August 2023, 45 from September–December 2023, and 53 from January–April 2024. While prescriptions for both celecoxib and other NSAIDs increased over time, the rate of celecoxib prescriptions showed a steeper rise. Conclusions: The findings demonstrate a notable increase in celecoxib prescriptions in this pain management clinic, outpacing the growth of other NSAIDs. This trend may reflect increasing provider preference for COX-2 selective inhibitors due to their favorable safety profile and efficacy. Further research is warranted to explore the underlying factors driving these prescribing patterns. Full article

Introduction: Epidural steroid injections (ESIs) are a common interventional treatment for managing spinal pain complaints. Despite their widespread use, practice patterns among physicians performing ESIs vary significantly. This study aimed to evaluate preprocedural imaging review by pain physicians who perform ESIs in the cervical, thoracic, and lumbar spine. Methods: A survey was distributed to a cohort of physicians who regularly perform ESIs. The survey comprised questions regarding preprocedural imaging review before performing ESIs in the cervical, thoracic, and lumbar spine. The respondents included a diverse group of pain management physicians from various specialties and practice settings. Results: The results revealed that the majority of interventional pain management physicians personally interpret their own imaging, followed by a significant percentage of physicians who rely on the radiology reports. There were no physicians who did not perform any imaging review prior to ESIs. Whereas all respondents reported some form of imaging review, only 63.86%, 53.75%, and 64.44% reviewed the actual images prior to cervical, thoracic, and lumbar access, respectively. Conclusions: This survey provides initial data regarding imaging reviews among physicians who perform ESIs. Our results demonstrate that physicians treat imaging review as an essential component of the preprocedural process for performing ESIs, as all physicians reported that they perform some form of imaging review before performing ESIs. However, there is only partial adherence to the multidisciplinary working group opinion that segmental imaging should be reviewed for adequacy of space prior to cervical epidural access. Full article

Background: While long-term opioid therapy is a widely utilized strategy for managing chronic pain, many patients have understandable questions and concerns regarding its safety, efficacy, and potential for dependency and addiction. Providing clear, accurate, and reliable information is essential for fostering patient understanding and acceptance. Generative artificial intelligence (AI) applications offer interesting avenues for delivering patient education in healthcare. This study evaluates the reliability, accuracy, and comprehensibility of ChatGPT’s responses to common patient inquiries about opioid long-term therapy. Methods: An expert panel selected thirteen frequently asked questions regarding long-term opioid therapy based on the authors’ clinical experience in managing chronic pain patients and a targeted review of patient education materials. Questions were prioritized based on prevalence in patient consultations, relevance to treatment decision-making, and the complexity of information typically required to address them comprehensively. We assessed comprehensibility by implementing the multimodal generative AI Copilot (Microsoft 365 Copilot Chat). Spanning three domains—pre-therapy, during therapy, and post-therapy—each question was submitted to GPT-4.0 with the prompt “If you were a physician, how would you answer a patient asking…”. Ten pain physicians and two non-healthcare professionals independently assessed the responses using a Likert scale to rate reliability (1–6 points), accuracy (1–3 points), and comprehensibility (1–3 points). Results: Overall, ChatGPT’s responses demonstrated high reliability (5.2 ± 0.6) and good comprehensibility (2.8 ± 0.2), with most answers meeting or exceeding predefined thresholds. Accuracy was moderate (2.7 ± 0.3), with lower performance on more technical topics like opioid tolerance and dependency management. Conclusions: While AI applications exhibit significant potential as a supplementary tool for patient education on opioid long-term therapy, limitations in addressing highly technical or context-specific queries underscore the need for ongoing refinement and domain-specific training. Integrating AI systems into clinical practice should involve collaboration between healthcare professionals and AI developers to ensure safe, personalized, and up-to-date patient education in chronic pain management. Full article

Background: Although spinal cord stimulation (SCS) is an effective treatment for managing chronic pain, many patients have understandable questions and concerns regarding this therapy. Artificial intelligence (AI) has shown promise in delivering patient education in healthcare. This study evaluates the reliability, accuracy, and comprehensibility of ChatGPT’s responses to common patient inquiries about SCS. Methods: Thirteen commonly asked questions regarding SCS were selected based on the authors’ clinical experience managing chronic pain patients and a targeted review of patient education materials and relevant medical literature. The questions were prioritized based on their frequency in patient consultations, relevance to decision-making about SCS, and the complexity of the information typically required to comprehensively address the questions. These questions spanned three domains: pre-procedural, intra-procedural, and post-procedural concerns. Responses were generated using GPT-4.0 with the prompt “If you were a physician, how would you answer a patient asking…”. Responses were independently assessed by 10 pain physicians and two non-healthcare professionals using a Likert scale for reliability (1–6 points), accuracy (1–3 points), and comprehensibility (1–3 points). Results: ChatGPT’s responses demonstrated strong reliability (5.1 ± 0.7) and comprehensibility (2.8 ± 0.2), with 92% and 98% of responses, respectively, meeting or exceeding our predefined thresholds. Accuracy was 2.7 ± 0.3, with 95% of responses rated sufficiently accurate. General queries, such as “What is spinal cord stimulation?” and “What are the risks and benefits?”, received higher scores compared to technical questions like “What are the different types of waveforms used in SCS?”. Conclusions: ChatGPT can be implemented as a supplementary tool for patient education, particularly in addressing general and procedural queries about SCS. However, the AI’s performance was less robust in addressing highly technical or nuanced questions. Full article

Cutaneous T-cell lymphoma (CTCL) is a rare T-cell malignancy characterized by inflamed and painful rash-like skin lesions that may affect large portions of the body’s surface. Patients experience recurrent infections due to a compromised skin barrier and generalized immunodeficiency resulting from a dominant Th2 immune phenotype of CTCL cells. Given the role of the unfolded protein response (UPR) in normal and malignant T-cell development, we investigated the impact of UPR-inducing drugs on the viability, transcriptional networks, and Th2 phenotype of CTCL. We found that CTCL cells were >5-fold more sensitive to the proteasome inhibitor bortezomib (Btz) and exhibited a distinct signaling and transcriptional response compared to normal CD4+ cells. The CTCL response was dominated by the induction of the HSP70 family member HSPA6 (HSP70B’) and, to a lesser extent, HSPA5 (BiP/GRP78). To understand the significance of these two factors, we used a novel isoform selective small-molecule inhibitor of HSPA5/6 (JG-023). JG-023 induced pro-apoptotic UPR signaling and enhanced the cytotoxic effects of proteasome inhibitors and other UPR-inducing drugs in CTCL but not normal T cells. Interestingly, JG-023 also selectively suppressed the production of Th2 cytokines in CTCL and normal CD4+ T cells. Conditioned media (CM) from CTCL were immunosuppressive to normal T cells through an IL-10-dependent mechanism. This immunosuppression could be reversed by JG-023, other HSP70 inhibitors, Btz, and combinations of these UPR-targeted drugs. Our study points to the importance of the UPR in the pathology of CTCL and demonstrates the potential of proteasome and targeted HSPA5/6 inhibitors for therapy. Full article

Background/Objectives: Anterior Gradient-2 (AGR2/PDIA17) is a member of the protein disulfide isomerase (PDI) family of oxidoreductases. AGR2 is up-regulated in several solid tumors, including pancreatic ductal adenocarcinoma (PDAC). Given the dire need for new therapeutic options for PDAC patients, we investigated the expression and function of AGR2 in PDAC and developed a novel series of affinity-matured AGR2-specific single-chain variable fragments (scFvs) and monoclonal antibodies. Results: We found that AGR2 was expressed in approximately 90% of PDAC but not normal pancreas biopsies, and the level of AGR2 expression correlated with increasing disease stage. AGR2 expression was inversely related to SMAD4 status in PDAC and colorectal cancer cell models and was secreted from cells into their media. In normal tissues, a high density of AGR2 was detected in the epithelium of cells in the digestive tract but was lacking in most other normal tissue systems. The addition of recombinant AGR2 to cell culture and genetic overexpression of AGR2 increased the adhesion, motility, and invasiveness of both human and mouse PDAC cells. Human phage display library screening led to the discovery of multiple AGR2-specific scFv clones that were affinity-matured to produce monoclonal antibody (MAb) clones with low picomolar binding affinity (S31R/A53F/Y). These high-affinity MAbs inhibited AGR2-mediated cell adhesion, migration, and binding to LYPD3, which is a putative cell surface binding partner of AGR2. Conclusions: Our study provides novel, high-affinity, fully human, anti-AGR2 MAbs that neutralize the pro-tumor effects of extracellular AGR2 in PDAC. Full article

(1) Background: Comprehensive and timely lung cancer (LC) staging is essential for prognosis and management. The Lung Diagnostic Assessment Program (LDAP) in Southeastern (SE) Ontario aims to provide rapid, guideline-concordant care for suspected LC patients. We evaluated factors affecting the completeness and timeliness of staging for stage I–III LC patients in SE Ontario, including the impact of LDAP management. (2) Methods: This was a population-based retrospective cohort study using the LDAP database (January 2017–December 2019), linked with the Ontario Cancer Registry, to identify newly diagnosed LC patients. A Cox model approach identified variables associated with staging completeness and timeliness. (3) Results: Among 755 patients, 459 (60.8%) were managed through LDAP. Optimal staging was achieved in 596 patients (78.9%), 23 (3.0%) had alternative staging, and 136 (18.0%) had incomplete staging. In the adjusted analyses, LDAP management was associated with a higher likelihood of complete staging (OR 2.29, p < 0.0001) and faster staging completion (β = −18.53, p < 0.0001). Increased distance to PET centres was associated with a longer time to complete staging (β = 8.95 per 100 km, p = 0.0007), as was longer time to diagnosis (β = 21.63 per 30 days, p < 0.0001). (4) Conclusions: LDAP management in SE Ontario significantly improved staging completeness and shortened staging time for stage I–III LC patients. Full article

The safety and immunogenicity of the two-dose Ebola vaccine regimen MVA-BN-Filo, Ad26.ZEBOV, 14 days apart, was evaluated in people without HIV (PWOH) and living with HIV (PLWH). In this observer-blind, placebo-controlled, phase 2 trial, healthy adults were randomized (4:1) to receive MVA-BN-Filo (dose 1) and Ad26.ZEBOV (dose 2), or two doses of saline/placebo, administered intramuscularly 14 days apart. The primary endpoints were safety (adverse events (AEs)) and immunogenicity (Ebola virus (EBOV) glycoprotein-specific binding antibody responses). Among 75 participants (n = 50 PWOH; n = 25 PLWH), 37% were female, the mean age was 44 years, and 56% were Black/African American. AEs were generally mild/moderate, with no vaccine-related serious AEs. At 21 days post-dose 2, EBOV glycoprotein-specific binding antibody responder rates were 100% among PWOH and 95% among PLWH; geometric mean antibody concentrations were 6286 EU/mL (n = 36) and 2005 EU/mL (n = 19), respectively. A total of 45 neutralizing and other functional antibody responses were frequently observed. Ebola-specific CD4+ and CD8+ T-cell responses were polyfunctional and durable to at least 12 months post-dose 2. The regimen was well tolerated and generated robust, durable immune responses in PWOH and PLWH. Findings support continued evaluation of accelerated vaccine schedules for rapid deployment in populations at immediate risk. Trial registration: NCT02598388 (submitted 14 November 2015). Full article

Neuromodulation is an alternative, minimally invasive treatment option that, at times, is used as a last resort for chronic pain conditions that are often refractory to other treatment modalities. Moreover, it offers promising prospects for individuals grappling with the formidable challenges posed by paraplegia and quadriplegia resulting from spinal cord injuries. This review article provides a comprehensive assessment of current treatment modalities specifically tailored for paraplegic and quadriplegic patients. We aim to evaluate the existing surgical and non-surgical interventions while delving into the role of neuromodulation in the restoration of function for individuals afflicted with these debilitating conditions. Additionally, we review the efficacy, limitations, and comparative outcomes of diverse treatment strategies available for the management of paraplegia and quadriplegia. Emphasizing the critical need for effective interventions beyond the initial 24 h surgical window, we elucidate the challenges associated with conventional therapies and their limited success in achieving comprehensive functional restoration. Central to this review is an in-depth exploration of neuromodulation’s transformative potential in ameliorating the deficits caused by spinal cord injuries. With a particular focus on spinal cord stimulation (SCS), we analyze and compare the outcomes of neuromodulation modalities and traditional treatment regimens, shedding light on the promising strides made in fostering sensory perception, motor function, and patient satisfaction. Full article

Peripheral artery disease (PAD) is caused by blocked arteries due to atherosclerosis and/or thrombosis which reduce blood flow to the lower limbs. It results in major morbidity, including ischemic limb, claudication, and amputation, with patients also suffering a heightened risk of heart attack, stroke, and death. Recent studies suggest women have a higher prevalence of PAD than men, and with worse outcomes after intervention. In addition to a potential unconscious bias faced by women with PAD in the health system, with underdiagnosis, and lower rates of guideline-based therapy, fundamental biological differences between men and women may be important. In this review, we highlight sexual dimorphisms in endothelial cell functions and how they may impact PAD pathophysiology in women. Understanding sex-specific mechanisms in PAD is essential for the development of new therapies and personalized care for patients with PAD. Full article

Enteric viruses are significant human pathogens that commonly cause foodborne illnesses worldwide. These viruses initiate infection in the gastrointestinal tract, home to a diverse population of intestinal bacteria. In a novel paradigm, data indicate that enteric viruses utilize intestinal bacteria to promote viral replication and pathogenesis. While mechanisms underlying these observations are not fully understood, data suggest that some enteric viruses bind directly to bacteria, stabilizing the virion to retain infectivity. Here, we discuss the current knowledge of these viral–bacterial interactions and examine the impact of these interactions on viral transmission. Full article