Crohn\'s disease is a chronic inflammatory bowel condition causing symptoms, notably pain, due to ongoing intestinal inflammation or complications like abscesses, strictures, and fistulas, which are common in IBD patients. Abdominal pain affects up to 60 % of IBD patients, irrespective of disease severity, prompting medical attention. Various medications like NSAIDs, antidepressants, antispasmodics, anticonvulsants, and opioids are used to manage pain, but they have limited effectiveness and potential side effects, even during remission. In this case, a 20-year-old Caucasian female college student [height 5\'4″, weight 120lbs (54.4 kg)] with juvenile idiopathic arthritis and Crohn\'s disease experienced severe daily abdominal pain, negatively impacting her life. Despite a multimodal regimen, including gabapentin, nortriptyline, duloxetine, and acetaminophen, her pain persisted, significantly affecting her appetite, sleep, mood, activity level, and overall quality of life (QOL). To address this, dorsal root ganglion (DRG) stimulation was considered. The patient aimed for a 20 % pain reduction and improved QOL. Trial leads were placed along the T10 and T12 DRG, resulting in a 25 % pain reduction (8-6 out of 10) and substantial QOL improvement. She could eat, sleep without interruptions, walk longer distances, and be more active. The T12 lead was more effective than the T10, targeting upper abdomen stimulation. The patient and her mother were highly satisfied and opted for permanent implantation for the T11 and T12 DRG. While DRG stimulation was approved in 2016 for chronic pain, to our knowledge, this is the first reported case of its use in a patient with debilitating Crohn\'s disease.

Background IL-1β plays a critical role in the pathophysiology of neuroinflammation. The presence of cleaved IL-1β (cIL-1β) in the neurons of the dorsal root ganglion (DRG) implicates its function in biological signaling arising from the sensory neuron. This study was conducted to analyze the role of IL-1β in nociceptive transduction after tissue injury. Methods A plantar incision was made in C57BL/6 mice, following which immunohistochemistry and RNA scope in situ hybridization were performed at various time points to analyze cIL-1β, caspase-1, and IL-1 receptor 1 (IL-1R1) expression in the DRG. The effect of intrathecal administration of a caspase-1 inhibitor or regional anesthesia using local anesthetics on cIL-1β expression and pain hypersensitivity was analyzed by immunohistochemistry and behavioral analysis. ERK phosphorylation was also analyzed to investigate the effect of IL-1β on the activity of spinal dorsal horn neurons. Results cIL-1β expression was significantly increased in caspase-1-positive DRG neurons 5 min after the plantar incision. Intrathecal caspase-1 inhibitor treatment inhibited IL-1β cleavage and pain hypersensitivity after the plantar incision. IL-1R1 was also detected in the DRG neurons, although the majority of IL-1R1-expressing neurons lacked cIL-1β expression. Regional anesthesia using local anesthetics prevented cIL-1β processing. Plantar incision-induced phosphorylation of ERK was inhibited by the caspase-1 inhibitor. Conclusion IL-1β in the DRG neuron undergoes rapid cleavage in response to tissue injury in an activity-dependent manner. Cleaved IL-1β causes injury-induced functional activation of sensory neurons and pain hypersensitivity. IL-1β in the primary afferent neurons is involved in physiological nociceptive signal transduction.

This study investigated the time course of gene expression changes during the progression of persistent painful neuropathy caused by paclitaxel (PTX) in male and female mouse hindpaws and dorsal root ganglia (DRG). Bulk RNA-seq was used to examine these gene expression changes at 1, 16, and 31 days post-last PTX. At these time points, differentially expressed genes (DEGs) were predominantly related to the reduction or increase in epithelial, skin, bone, and muscle development and to angiogenesis, myelination, axonogenesis, and neurogenesis. These processes are accompanied by the regulation of DEGs related to the cytoskeleton, extracellular matrix organization, and cellular energy production. This gene plasticity during the progression of persistent painful neuropathy could be interpreted as a biological process linked to tissue regeneration/degeneration. In contrast, gene plasticity related to immune processes was minimal at 1-31 days after PTX. It was also noted that despite similarities in biological processes and pain chronicity between males and females, specific DEGs differed dramatically according to sex. The main conclusions of this study are that gene expression plasticity in hindpaw and DRG during PTX neuropathy progression similar to tissue regeneration and degeneration, minimally affects immune system processes and is heavily sex-dependent at the individual gene level.

In tumor cells, interleukin-6 (IL-6) signaling can lead to activation of the epidermal growth factor receptor (EGFR), which prolongs Stat3 activation. In the present experiments, we tested the hypothesis that IL-6 signaling activates EGFR signaling in peripheral and spinal nociception and examined whether EGFR localization and activation coincide with pain-related behaviors in arthritis. In vivo in anesthetized rats, spinal application of the EGFR receptor blocker gefitinib reduced the responses of spinal cord neurons to noxious joint stimulation, but only after spinal pretreatment with IL-6 and soluble IL-6 receptor. Using Western blots, we found that IL-6-induced Stat3 activation was reduced by gefitinib in microglial cells of the BV2 cell line, but not in cultured DRG neurons. Immunohistochemistry showed EGFR localization in most DRG neurons from normal rats, but significant downregulation in the acute and most painful arthritis phase. In the spinal cord of mice, EGFR was highly activated mainly in the chronic phase of inflammation, with localization in neurons. These data suggest that spinal IL-6 signaling may activate spinal EGFR signaling. Downregulation of EGFR in DRG neurons in acute arthritis may limit nociception, but pronounced delayed activation of EGFR in the spinal cord may be involved in chronic inflammatory pain.

UNASSIGNED: Diagnosis-related group (DRG) payment policies are increasingly recognized as crucial instruments for addressing health care overprovision and escalating health care costs. The synthetic control method (SCM) has emerged as a robust tool for evaluating the efficacy of health policies worldwide.
UNASSIGNED: This study focused on Panzhihua city in Sichuan Province, a pilot city for DRG payment reform implementation, serving as the treatment group. In contrast, 20 nonpilot cities within the province were utilized as potential control units. A counterfactual control group was constructed to evaluate the changes in average inpatient stay duration and health care organization costs following the DRG payment reform initiated in 2018.
UNASSIGNED: Focusing on Panzhihua, Sichuan Province, the analysis reveals that following the reform in March 2018, the average length of hospital stay in Panzhihua decreased by 1.35 days during 2019-2021. Additionally, the average cost per hospitalization dropped by 855.48 RMB, the average cost of medication per hospitalization decreased by 68.51 RMB, and the average cost of diagnostic and therapeutic procedures per hospitalization declined by 136.37 RMB. While global evidence backs DRGs for efficiency and cost reduction, challenges persist in addressing emerging issues like new conditions.
UNASSIGNED: Since its introduction in 2018, the DRG payment reform in Sichuan Province has effectively reduced both the duration of hospital stays and the operational costs of health care facilities. However, potential drawbacks include compromised service quality and an elevated risk of patient readmission, indicating a need for further refinement in the implementation of DRG payment reforms in China.

Targeting the CCL2/CCR2 chemokine axis has been shown to be effective at relieving pain in rodent models of inflammatory and neuropathic pain, therefore representing a promising avenue for the development of non-opioid analgesics. However, clinical trials targeting this receptor for inflammatory conditions and painful neuropathies have failed to meet expectations and have all been discontinued due to lack of efficacy. To overcome the poor selectivity of CCR2 chemokine receptor antagonists, we generated and characterized the function of intracellular cell-penetrating allosteric modulators targeting CCR2, namely pepducins. In vivo, chronic intrathecal administration of the CCR2-selective pepducin PP101 was effective in alleviating neuropathic and bone cancer pain. In the setting of bone metastases, we found that T cells infiltrate dorsal root ganglia (DRG) and induce long-lasting pain hypersensitivity. By acting on CCR2-expressing DRG neurons, PP101 attenuated the altered phenotype of sensory neurons as well as the neuroinflammatory milieu of DRGs, and reduced bone cancer pain by blocking CD4+ and CD8+ T cell infiltration. Notably, PP101 demonstrated its efficacy in targeting the neuropathic component of bone cancer pain, as evidenced by its anti-nociceptive effects in a model of chronic constriction injury of the sciatic nerve. Importantly, PP101-induced reduction of CCR2 signaling in DRGs did not result in deleterious tumor progression or adverse behavioral effects. Thus, targeting neuroimmune crosstalk through allosteric inhibition of CCR2 could represent an effective and safe avenue for the management of chronic pain.

Hyperalgesia is typified by reduced pain thresholds and heightened responses to painful stimuli, with a notable prevalence in menopausal women, but the underlying mechanisms are far from understood. β-Aminoisobutyric acid (BAIBA), a product of valine and thymine catabolism, has been reported to be a novel ligand of the Mas-related G protein coupled receptor D (MrgprD), which mediates pain and hyperalgesia. Here, we established a hyperalgesia model in 8-week-old female mice through ovariectomy (OVX). A significant increase in BAIBA plasma level was observed and was associated with decline of mechanical withdrawal threshold, thermal and cold withdrawal latency in mice after 6 weeks of OVX surgery. Increased expression of MrgprD in dorsal root ganglion (DRG) was shown in OVX mice compared to Sham mice. Interestingly, chronic loading with BAIBA not only exacerbated hyperalgesia in OVX mice, but also induced hyperalgesia in gonadally intact female mice. BAIBA supplementation also upregulated the MrgprD expression in DRG of both OVX and intact female mice, and enhanced the excitability of DRG neurons in vitro. Knockout of MrgprD markedly suppressed the effects of BAIBA on hyperalgesia and excitability of DRG neurons. Collectively, our data suggest the involvement of BAIBA in the development of hyperalgesia via MrgprD-dependent pathway, and illuminate the mechanisms underlying hyperalgesia in menopausal women.

UNASSIGNED: Nav1.8 expression is restricted to sensory neurons; it was hypothesized that aberrant expression and function of this channel at the site of injury contributed to pathological pain. However, the specific contributions of Nav1.8 to neuropathic pain are not as clear as its role in inflammatory pain. The aim of this study is to understand how Nav1.8 present in peripheral sensory neurons regulate neuronal excitability and induce various electrophysiological features on neuropathic pain.
UNASSIGNED: To study the effect of changes in sodium channel Nav1.8 kinetics, Hodgkin-Huxley type conductance-based models of spiking neurons were constructed using the NEURON v8.2 simulation software. We constructed a single-compartment model of neuronal soma that contained Nav1.8 channels with the ionic mechanisms adapted from some existing small DRG neuron models. We then validated and compared the model with our experimental data from in vivo recordings on soma of small dorsal root ganglion (DRG) sensory neurons in animal models of neuropathic pain (NEP).
UNASSIGNED: We show that Nav1.8 is an important parameter for the generation and maintenance of abnormal neuronal electrogenesis and hyperexcitability. The typical increased excitability seen is dominated by a left shift in the steady state of activation of this channel and is further modulated by this channel\'s maximum conductance and steady state of inactivation. Therefore, modified action potential shape, decreased threshold, and increased repetitive firing of sensory neurons in our neuropathic animal models may be orchestrated by these modulations on Nav1.8.
UNASSIGNED: Computational modeling is a novel strategy to understand the generation of chronic pain. In this study, we highlight that changes to the channel functions of Nav1.8 within the small DRG neuron may contribute to neuropathic pain.

Endosomal trafficking of TrkA is a critical process for nerve growth factor (NGF)-dependent neuronal cell survival and differentiation. The small GTPase ADP-ribosylation factor 6 (Arf6) is implicated in NGF-dependent processes in PC12 cells through endosomal trafficking and actin cytoskeleton reorganization. However, the regulatory mechanism for Arf6 in NGF signaling is largely unknown. In this study, we demonstrated that EFA6A, an Arf6-specific guanine nucleotide exchange factor, was abundantly expressed in PC12 cells and that knockdown of EFA6A significantly inhibited NGF-dependent Arf6 activation, TrkA recycling from early endosomes to the cell surface, prolonged ERK1/2 phosphorylation, and neurite outgrowth. We also demonstrated that EFA6A forms a protein complex with TrkA through its N-terminal region, thereby enhancing its catalytic activity for Arf6. Similarly, we demonstrated that EFA6A forms a protein complex with TrkA in cultured dorsal root ganglion (DRG) neurons. Furthermore, cultured DRG neurons from EFA6A knockout mice exhibited disturbed NGF-dependent TrkA trafficking compared with wild-type neurons. These findings provide the first evidence for EFA6A as a key regulator of NGF-dependent TrkA trafficking and signaling.

Background/Objectives: Aneurysms and dissections of the iliac artery (ADIAs) are significant vascular conditions often associated with aortic pathologies. Despite their importance, reports on isolated iliac artery pathologies are rare. This study aimed to investigate the epidemiology of ADIA in Switzerland including treatment incidence and hospital outcomes. Methods: A retrospective analysis of diagnosis-related group (DRG) statistics from 2011 to 2018 in Switzerland was conducted, identifying all cases of ADIA while excluding those with concomitant treatment of aortic pathologies. Age-standardized incidence rates and treatment outcomes were assessed, with multivariable logistic regression performed to identify factors associated with hospital mortality. Results: From 2011 to 2018, 1037 ADIA cases were hospitalized in Switzerland. Incidence rates for elective treatment were significantly higher in men than women, increasing in men from 1.5 to 2.4 cases per 100,000 men (p = 0.007), while remaining stable in women at around 0.2 cases per 100,000 women. Acute treatment incidence rates were lower but still higher in men, at 0.9 cases per 100,000 men and 0.2 cases per 100,000 women. Crude hospital mortality rates were lower for endovascular repair than open surgical repair in both elective (0.8% vs. 3.1%, p = 0.023) and emergency treatment (6.7% vs. 18.4%, p = 0.045). Multivariable analysis showed that endovascular repair was associated with significantly reduced hospital mortality compared to open repair (OR 0.27, 95%-CI: 0.10 to 0.66, p = 0.006). Conclusions: This nationwide study of iliac artery pathologies shows that the treatment incidence was about 10 times higher in men than in women for elective procedures, but only about five times higher for emergency treatment. Endovascular procedures were associated with significantly lower hospital mortality than open procedures, while hospital mortality rates were comparable for men and women.