Impact of Diagnosis-Related Groups (DRG) reform on cost homogeneity of treatment for patients with malignant tumours.

The cost fluctuations associated with chemotherapy, radiotherapy, and immunotherapy, as primary modalities for treating malignant tumors, are closely related to medical decision-making and impose financial burdens on patients. In response to these challenges, China has implemented the Diagnosis-Related Group (DRG) payment system to standardize costs and control expenditures. This study collected hospitalization data from patients with malignant tumors who received chemotherapy, radiotherapy, and immunotherapy at Hospital H from 2018 to 2022. The dataset was segmented into two groups: the intervention group, treated with traditional Chinese medicine (TCM) alongside standard therapies, and the control group, treated with standard therapies alone. Changes and trends in hospitalization costs under the DRG policy were analyzed using propensity-score matching (PSM), standard deviation (SD), interquartile range (IQR), and concentration index (CI). Findings showed a decreasing trend in the standard deviation of hospitalization costs across all treatment modalities. Radiotherapy exhibited the most significant decrease, with costs reducing by 2547.37 CNY in the control group and 7387.35 CNY in the intervention group. Following the DRG implementation, the concentration indexes for chemotherapy and radiotherapy increased, while those for immunotherapy did not exhibit this pattern. Costs were more concentrated in patients who did not receive TCM treatment. In summary, DRG reform positively impacted the cost homogeneity of inpatient treatments for malignant tumors, particularly in the control group not receiving TCM treatment. The effects of DRG reform varied across different treatment modalities. Although short-term fluctuations in hospitalization costs may occur, initial evidence during the study period shows the positive impact of DRG reform on cost homogeneity.

Regulation of Kv1.2 redox-sensitive gating by the transmembrane lectin LMAN2.

Kv1.2 potassium channels influence excitability and action potential propagation in the nervous system. Unlike closely-related Kv1 channels, Kv1.2 exhibits highly variable voltage-dependence of gating, attributed to regulation by unidentified extrinsic factors. Variability of Kv1.2 gating is strongly influenced by the extracellular redox potential, and we demonstrate that Kv1.2 currents in dorsal root ganglion sensory neurons exhibit similar variability and redox sensitivity as observed when the channel is heterologously expressed in cell lines. We used a functional screening approach to test the effects of candidate regulatory proteins on Kv1.2 gating, using patch clamp electrophysiology. Among 52 candidate genes tested, we observed that co-expression with the transmembrane lectin LMAN2 led to a pronounced gating shift of Kv1.2 activation to depolarized voltages in CHO and L(tk-) cell lines, accompanied by deceleration of activation kinetics. Overexpression of LMAN2 promoted a slow gating mode of Kv1.2 that mimics the functional outcomes of extracellular reducing conditions, and enhanced sensitivity to extracellular reducing agents. In contrast, shRNA-mediated knockdown of endogenous LMAN2 in cell lines reduced Kv1.2 redox sensitivity and gating variability. Kv1.2 sensitivity to LMAN2 is abolished by mutation of neighboring residues F251 and T252 in the intracellular S2-S3 linker, and these also abolish redox-dependent gating changes, suggesting that LMAN2 influences the same pathway as redox for Kv1.2 modulation. In conclusion, we identified LMAN2 as a candidate regulatory protein that influences redox-dependent modulation of Kv1.2, and clarified the structural elements of the channel that are required for sensitivity.

Dorsal root ganglion inflammation by oxaliplatin toxicity: DPEP1 as possible target for peripheral neuropathy prevention.

BACKGROUND: Peripheral neuropathy (PN) constitutes a dose-limiting side effect of oxaliplatin chemotherapy that often compromises the efficacy of antineoplastic treatments. Sensory neurons damage in dorsal root ganglia (DRG) are the cellular substrate of PN complex molecular origin. Dehydropeptidase-1 (DPEP1) inhibitors have shown to avoid platin-induced nephrotoxicity without compromising its anticancer efficiency. The objective of this study was to describe DPEP1 expression in rat DRG in health and in early stages of oxaliplatin toxicity. To this end, we produced and characterized anti-DPEP1 polyclonal antibodies and used them to define the expression, and cellular and subcellular localization of DPEP1 by immunohistochemical confocal microscopy studies in healthy controls and short term (six days) oxaliplatin treated rats. RESULTS: DPEP1 is expressed mostly in neurons and in glia, and to a lesser extent in endothelial cells. Rats undergoing oxaliplatin treatment developed allodynia. TNF-𝛼 expression in DRG revealed a pattern of focal and at different intensity levels of neural cell inflammatory damage, accompanied by slight variations in DPEP1 expression in endothelial cells and in nuclei of neurons. CONCLUSIONS: DPEP1 is expressed in neurons, glia and endothelial cells of DRG. Oxaliplatin caused allodynia in rats and increased TNF-α expression in DRG neurons. The expression of DPEP1 in neurons and other cells of DRG suggest this protein as a novel strategic molecular target in the prevention of oxaliplatin-induced acute neurotoxicity.

Diagnosis-Related Groups payment reform and hospital cost control.

BACKGROUND: This study explores the influence of Diagnosis-Related Groups (DRG) payment reform on hospital cost control and offers pertinent cost management strategies for public hospitals. It situates the research by elucidating the significance of the DRG payment method and comparing its advantages and drawbacks with the traditional 'pay per project' model. OBJECTIVE: The primary aim is to assess the impact of DRG payment reform on hospital cost control and propose effective cost management strategies for public hospitals. The objective is to provide insights into DRG payment implications and attempt practical recommendations for its implementation in the public healthcare sector. METHODS: Employing a comprehensive approach, the study analyzes DRG payment, delineates advantages and drawbacks, and proposes cost management strategies. Methods include staff training, an information management platform, disease analysis, and optimized cost accounting. The study highlights the potential for improved medical diagnosis and treatment through industry-finance integration. RESULTS: Findings reveal advantages and limitations of DRG payment, emphasizing strategies for optimizing hospital operations. Enhanced medical diagnosis and treatment procedures through industry-finance integration contribute to overall cost control effectiveness. CONCLUSION: The study serves as a practical guide for implementing DRG payment reforms, offering valuable insights for policymakers and healthcare professionals in navigating the complexities of cost control in public healthcare.

Case Report: Rescue of Relapsed Pain in a Patient with Complex Regional Pain Syndrome Type II by Adding Another Dorsal Root Ganglion Lead.

We present on a patient with complex regional pain syndrome (CRPS) following ankle surgery. Pain was refractory to both conservative and surgical measures including neurotomies, ankle fusion, hardware removal, and spinal cord stimulation (SCS) trial. A dorsal root ganglion (DRG) stimulation trial with lead placements at L4, L5, and S1 provided significant pain and functional improvement. However, during the implantation, we were able to place only two DRG leads at L4 and L5 and not S1 due to difficulties with advancing the lead to the desired location. Nonetheless, the two DRG leads provided 90% pain relief and 75% functional improvement for 9 months. However, the patient experienced pain symptoms similar to that of pre-implant without a clear trigger after 9 months despite no DRG stimulator hardware malfunction or lead migration. A decision was made to re-try implanting the S1 DRG lead, which was successful and provided significant pain relief.

Substrate selectivity and inhibition of the human lysyl hydroxylase JMJD7.

Jumonji-C (JmjC) domain-containing protein 7 (JMJD7) is a human Fe(II) and 2-oxoglutarate dependent oxygenase that catalyzes stereospecific C3-hydroxylation of lysyl-residues in developmentally regulated GTP binding proteins 1 and 2 (DRG1/2). We report studies exploring a diverse set of lysine derivatives incorporated into the DRG1 peptides as potential human JMJD7 substrates and inhibitors. The results indicate that human JMJD7 has a relatively narrow substrate scope beyond lysine compared to some other JmjC hydroxylases and lysine-modifying enzymes. The geometrically constrained (E)-dehydrolysine is an efficient alternative to lysine for JMJD7-catalyzed C3-hydroxylation. γ-Thialysine and γ-azalysine undergo C3-hydroxylation, followed by degradation to formylglycine. JMJD7 also catalyzes the S-oxidation of DRG1-derived peptides possessing methionine and homomethionine residues in place of lysine. Inhibition assays show that DRG1 variants possessing cysteine/selenocysteine instead of the lysine residue efficiently inhibit JMJD7 via cross-linking. The overall results inform on the substrate selectivity and inhibition of human JMJD7, which will help enable the rational design of selective small-molecule and peptidomimetic inhibitors of JMJD7.

Protein phosphatase 2Cm-regulated branched-chain amino acid catabolic defect in dorsal root ganglion neurons drives pain sensitization.

Maladaptive changes of metabolic patterns in the lumbar dorsal root ganglion (DRG) are critical for nociceptive hypersensitivity genesis. The accumulation of branched-chain amino acids (BCAAs) in DRG has been implicated in mechanical allodynia and thermal hyperalgesia, but the exact mechanism is not fully understood. This study aimed to explore how BCAA catabolism in DRG modulates pain sensitization. Wildtype male mice were fed a high-fat diet (HFD) for 8 weeks. Adult PP2Cmfl/fl mice of both sexes were intrathecally injected with pAAV9-hSyn-Cre to delete the mitochondrial targeted 2 C-type serine/threonine protein phosphatase (PP2Cm) in DRG neurons. Here, we reported that BCAA catabolism was impaired in the lumbar 4-5 (L4-L5) DRGs of mice fed a high-fat diet (HFD). Conditional deletion of PP2Cm in DRG neurons led to mechanical allodynia, heat and cold hyperalgesia. Mechanistically, the genetic knockout of PP2Cm resulted in the upregulation of C-C chemokine ligand 5/C-C chemokine receptor 5 (CCL5/CCR5) axis and an increase in transient receptor potential ankyrin 1 (TRPA1) expression. Blocking the CCL5/CCR5 signaling or TRPA1 alleviated pain behaviors induced by PP2Cm deletion. Thus, targeting BCAA catabolism in DRG neurons may be a potential management strategy for pain sensitization.

Dorsal root ganglion stimulation provides significant functional improvement from acute debilitating Crohn's disease: A novel use.

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.

Interleukin-6 induces nascent protein synthesis in human dorsal root ganglion nociceptors primarily via MNK-eIF4E signaling.

Plasticity of dorsal root ganglion (DRG) nociceptors in the peripheral nervous system requires new protein synthesis. This plasticity is believed to be responsible for the physiological changes seen in DRG nociceptors in animal models of chronic pain. Experiments in human DRG (hDRG) neurons also support this hypothesis, but a direct observation of nascent protein synthesis in response to a pain promoting substance, like interleukin-6 (IL-6), has not been measured in these neurons. To fill this gap in knowledge, we used acutely prepared human DRG explants from organ donors. These explants provide a physiologically relevant microenvironment, closer to in vivo conditions, allowing for the examination of functional alterations in DRG neurons reflective of human neuropathophysiology. Using this newly developed assay, we demonstrate upregulation of the target of the MNK1/2 kinases, phosphorylated eIF4E (p-eIF4E), and nascently synthesized proteins in a substantial subset of hDRG neurons following exposure to IL-6. To pinpoint the specific molecular mechanisms driving this IL-6-driven increase in nascent proteins, we used the specific MNK1/2 inhibitor eFT508. Treatment with eFT508 resulted in the inhibition of IL-6-induced increases in p-eIF4E and nascent proteins. Additionally, using TRPV1 as a marker for nociceptors, we found that these effects occurred in a large number of human nociceptors. Our findings provide clear evidence that IL-6 drives nascent protein synthesis in human TRPV1+ nociceptors primarily via MNK1/2-eIF4E signaling. The work links animal findings to human nociception, creates a framework for additional hDRG signaling experiments, and substantiates the continued development of MNK inhibitors for pain.

Non-integrin laminin receptor (LamR) plays a role in axonal outgrowth from chicken DRG via modulating the Akt and Erk signaling.

37/67 kDa laminin receptor (LamR)/ribosomal protein SA exhibits dual function as both a ribosomal protein and cell surface receptor for laminin. LamR influences critical cellular processes such as invasion, adhesion, and migration when acting as a receptor. Despite the acknowledged importance of LamR/67LR in various cellular processes, its contribution to the peripheral nervous system development is obscure. Thus, this study investigated the biological activity of LamR in peripheral axonal outgrowth in the presence of laminin-1 or Ile-Lys-Val-Ala-Val (IKVAV) peptide, whose important role in dorsal root ganglia (DRG) axonal outgrowth we recently showed. Unexpectedly, we did not observe LamR on the surface of DRG cells or in a conditioned medium, suggesting its intracellular action in the negative regulation of DRG axonal outgrowth. Using C-terminus LamR-targeting IgG, we demonstrated the role of LamR in that process, which is independent of the presence of Schwann cell precursors (SCPs) and is mediated by extracellular signal-regulated kinase (Erk) and Protein kinase B (Akt1/2/3) signaling pathways. Additionally, we show that the action of LamR towards laminin-1-dependent axonal outgrowth is unmasked only when the activity of integrin ß1 is perturbed. We believe that modulation of LamR activity provides the basis for its use for inhibiting axon growth as a potential therapeutic agent for regulating abnormal or excessive neurite growth during neurodevelopmental diseases or pathological nerve regeneration.

Complementary and integrative medicine - Resolving situations of reduced remuneration for additional work under the SwissDRG system.

Aim of the study: Complementary and integrative medicine (CIM) has been increasingly recognized as offering promising treatment adjunctions in various clinical settings, even amongst patients with serious, chronic, or recurrent illness. Today, only few tertiary care facilities in Switzerland offer dedicated CIM services for inpatients. The aim of the present study was to evaluate whether CIM services for complex medical conditions are adequately valued by the national inpatient SwissDRG reimbursement system. Methods: A simulation was performed by adding a specific code of the Swiss classification of interventions (CHOP) to the list of codes of each patient who received CIM therapies at the Lausanne University Hospital (CHUV) in 2021. This code is to be used when CIM services are provided. Hitherto, it was not entered due to a lack of specific documents justifying the resources used. The analysis focused on the impact of adding this CIM CHOP code on the Swiss Diagnosis Related Group (DRG) reimbursement. Results: In total, 275 patients received a CIM therapy in 2021. The addition of the CIM CHOP code 99.BC.12 (10-25 CIM sessions per stay) resulted in a simulated loss of income of CHF 766 630 for the hospital, while the net real result is already negative by more than CHF 6 million. The DRGs positively impacted by the addition of CIM CHOP code 99.BC.12 had a mean (SD) cost weight (CW) of 1.014 (0.620), while the DRGs negatively impacted had a mean (SD) CW of 3.97 (2.764) points. Conclusion: It is necessary to quickly react and improve the incentives contained in the grouping algorithm of the prospective payment system, whose effects can threaten the provision of adequate medical care to the patients despite suitable indications and potential for cost-savings.

Quercetin/polyethyleneimine modified gold nanoconjugates inhibit apoptosis and ROS production induced by hydrogen peroxide in DRG sensory neurons.

The basis of most neurological syndromes is the accumulation of free radical molecules. Quercetin is a polyphenolic bioflavonoid molecule and it has a very strong antioxidant effect by maintaining oxidative balance. There are many difficulties in the clinical use of quercetin due to its hydrophobic structure, low solubility, instability, poor oral bioavailability, and limited tissue-barrier penetration. Its synergistic use in complex with gold nanoparticles (AuNPs) could overcome these problems. AuNPs have recently emerged as an attractive candidate for delivery applications of various biomolecules and drugs. The aim of this study was to synthesize two different sized gold nanoparticles (AuNP20 and AuNP50) modified with polyethyleneimine (PEI) and quercetin, evaluate their potential neuroprotective effects on the in vitro oxidative stress model using DRG primary sensory neurons. It was shown that the antioxidant and anti-apoptotic ability of the bioflavonoid was preserved after exposure to the designed quercetin modified AuNPs. The PEI surface coating increased the stability and biocompatibility of the AuNPs in both sizes. It also potentially enables additional surface functionalization. This study indicates that designed nanoparticles (AuNP-Q-PEI) with different sizes could be a useful potential platform for the treatment of neurodegenerative syndromes or cancer diseases.

Isolation and Culture of Adult Rat Dorsal Root Ganglion Neurons for the In Vitro Analysis of Peripheral Nerve Degeneration and Regeneration.

Isolation and culture of dorsal root ganglion (DRG) neurons from adult animals is a useful experimental system for evaluating neural plasticity after axonal injury, as well as the neurological dysfunction resulting from aging and various types of disease. In this chapter, we will introduce a detailed method for the culture of mature rat DRG neurons. About 30-40 ganglia are dissected from a rat and mechanically and enzymatically digested. Subsequently, density gradient centrifugation of the digested tissue using 30% Percoll efficiently eliminates myelin debris and non-neuronal cells, to afford neuronal cells with a high yield and purity.

Efficacy of Mind-Regulating and Depression-Reliving Acupuncture in Combination with Radiofrequency Thermocoagulation of Dorsal Root Ganglion for Post-herpetic Neuralgia.

PURPOSE: This study is aimed at evaluating the efficacy of mind-regulating and depression-relieving acupuncture in combination with radiofrequency thermocoagulation of dorsal root ganglion (DRG) for post-herpetic neuralgia (PHN). METHODS: PHN patients who presented to the Pain Department of Affiliated Hospital of Jiaxing University from November 2021 to June 2023 were included. The participants were assigned into 2 groups using a random number table: Acupuncture + RFTC (group H, n = 44) group and RFTC (group C, n = 44) group. The pain numerical rating score (NRS), visual analogue scale scores (VAS), IL-6, Gal-3, oral dose of tramadol and gabapentin capsules levels were recorded before and after 1, 2, 4, 8 and 12 weeks of the treatment. RESULTS: After treatment, NRS scores in both groups were significantly lower than pretreatment scores at each time point. Compared with before treatment, the VAS scores at all time points after treatment was increased in both groups. Compared with before treatment, the doses of oral gabapentin capsules and tramadol were reduced in both groups after treatment. Compared with group C, the doses of oral gabapentin capsules and tramadol after the end of the treatment course were significantly reduced in group H. Compared with before treatment, the blood levels of Gal-3 and IL-6 were reduced at all points after treatment in both groups. Compared with group C, the blood Gal-3 and IL-6 levels were significantly reduced in group H. CONCLUSIONS: Compared with RFTC alone, acupuncture combined with RFTC of DRG has a better therapeutic effect for PHN.

Tomivosertib reduces ectopic activity in dorsal root ganglion neurons from patients with radiculopathy.

Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in patients suffering from this largely untreated disease. While many intracellular signalling mechanisms have been examined in preclinical models that drive spontaneous activity, none have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we showed that inhibition of mitogen-activated protein kinase interacting kinase (MNK) with tomivosertib (eFT508, 25 nM) reversibly suppresses spontaneous activity in human sensory neurons that are likely nociceptors based on size and action potential characteristics associated with painful dermatomes within minutes of treatment. Tomivosertib treatment also decreased action potential amplitude and produced alterations in the magnitude of after hyperpolarizing currents, suggesting modification of Na+ and K+ channel activity as a consequence of drug treatment. Parallel to the effects on electrophysiology, eFT508 treatment led to a profound loss of eIF4E serine 209 phosphorylation in primary sensory neurons, a specific substrate of MNK, within 2 min of drug treatment. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain.

Anoctamin 1, a multi-modal player in pain and itch.

Anoctamin 1 (ANO1/TMEM16A) encodes a Ca2+-activated Cl- channel. Among ANO1's many physiological functions, it plays a significant role in mediating nociception and itch. ANO1 is activated by intracellular Ca2+ and depolarization. Additionally, ANO1 is activated by heat above 44 °C, suggesting heat as another activation stimulus. ANO1 is highly expressed in nociceptors, indicating a role in nociception. Conditional Ano1 ablation in dorsal root ganglion (DRG) neurons results in a reduction in acute thermal pain, as well as thermal and mechanical allodynia or hyperalgesia evoked by inflammation or nerve injury. Pharmacological interventions also lead to a reduction in nocifensive behaviors. ANO1 is functionally linked to the bradykinin receptor and TRPV1. Bradykinin stimulates ANO1 via IP3-mediated Ca2+ release from intracellular stores, whereas TRPV1 stimulates ANO1 via a combination of Ca2+ influx and release. Nerve injury causes upregulation of ANO1 expression in DRG neurons, which is blocked by ANO1 antagonists. Due to its role in nociception, strong and specific ANO1 antagonists have been developed. ANO1 is also expressed in pruritoceptors, mediating Mas-related G protein-coupled receptors (Mrgprs)-dependent itch. The activation of ANO1 leads to chloride efflux and depolarization due to high intracellular chloride concentrations, causing pain and itch. Thus, ANO1 could be a potential target for the development of new drugs treating pain and itch.

Impact of Interleukin-6 Activation and Arthritis on Epidermal Growth Factor Receptor (EGFR) Activation in Sensory Neurons and the Spinal Cord.

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.

Predictors of Outcomes in Cerebellar Stroke: A Retrospective Cohort Study From the National Inpatient Sample Data.

Cerebellar strokes have high morbidity and mortality due to bleeding or edema, leading to increased pressure in the posterior fossa. This retrospective cohort study analyzed three outcomes following a cerebellar stroke: in-hospital mortality, length of hospital stay, and total hospitalization costs. It uses data from the National Inpatient Sample (NIS) and aims to identify the predictors of outcomes in cerebellar stroke patients, including 464,324 patients, 18 years of age and older, hospitalized between 2010 and 2015 in US hospitals with cerebellar strokes. In our study, for every decade age increased beyond 59 years, there was a significant increase in mortality; those aged 80+ years had 5.65 odds of mortality (95% CI: 5.32-6.00; P < 0.0001). Significant differences in patient characteristics were observed between patients who survived to discharge and those who did not, including older age (77.4 vs. 70.3 years; P < 0.0001), female sex (58% vs. 52%; P < 0.0001), and being transferred from another healthcare facility (17% vs. 10%; P < 0.0001). Patients admitted directly rather than through the emergency department were more likely to die (29% vs. 16%; P < 0.0001). The mortality rate was lower for blacks (OR: 0.75; P < 0.0001), Hispanics (OR: 0.91; P = 0.005), and Asians (OR: 0.89; P = 0.03), as compared to the white population, for females in comparison to males, and geographically, in all other areas (Midwest, South, and West) in contrast to the Northeast. Cerebellar stroke incidence and high mortality were seen in the traditional stroke belt. Mortality is also affected by the severity of the disease and increases with the Charlson Comorbidity Index (CCI), All Patient Refined Diagnosis Related Groups (APR-DRG) scores, and indirectly by place of receiving care, length of stay (LOS), cost of stay, type of insurance, and emergency department admissions. LOS increased with age, in males in the Northeast, and was less in whites compared to other races. Trend analysis showed a decrease in LOS and costs from 2010 to 2015. Increased costs were seen in non-whites, males, higher household income based on zip code, being covered under Medicaid, transfers, CCI ≥ 5, and discharges in the western US. Median household income based on the patient's zip code was well-balanced between those who lived and those who died (P = 0.091). However, payers were not evenly distributed between the two groups (P < 0.0001 for the overall comparison). A higher proportion of discharges associated with in-hospital mortality were covered under Medicare (70% vs. 65% in the died vs. lived groups, respectively). Fewer discharges were associated with death if they were covered by commercial insurance or paid for out-of-pocket (15% vs. 19% for commercial insurance and 3% vs. 5% for out-of-pocket). In-hospital mortality was associated with a longer length of hospital stay (5.6 days vs. 4.5 days; P < 0.0001) and higher costs ($16,815 vs. $11,859; P < 0.0001). Variables that were significantly associated with lower total costs were older age, having commercial insurance, paying out-of-pocket or other payers, not being admitted through the emergency department, having a lower comorbidity index (CCI = 1-2), and being discharged from a hospital that was small- or medium-sized, located in the Midwest or South, and/or was non-teaching (rural or urban).

Adenosine A2B receptors differently modulate oligodendrogliogenesis and myelination depending on their cellular localization.

Differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs) is a key event for axonal myelination in the brain; this process fails during demyelinating pathologies. Adenosine is emerging as an important player in oligodendrogliogenesis, by activating its metabotropic receptors (A1R, A2AR, A2BR, and A3R). We previously demonstrated that the Gs-coupled A2BR reduced differentiation of primary OPC cultures by inhibiting delayed rectifier (IK) as well as transient (IA) outward K+ currents. To deepen the unclear role of this receptor subtype in neuron-OL interplay and in myelination process, we tested the effects of different A2BR ligands in a dorsal root ganglion neuron (DRGN)/OPC cocultures, a corroborated in vitro myelination assay. The A2BR agonist, BAY60-6583, significantly reduced myelin basic protein levels but simultaneously increased myelination index in DRGN/OPC cocultures analyzed by confocal microscopy. The last effect was prevented by the selective A2BR antagonists, PSB-603 and MRS1706. To clarify this unexpected data, we wondered whether A2BRs could play a functional role on DRGNs. We first demonstrated, by immunocytochemistry, that primary DRGN monoculture expressed A2BRs. Their selective activation by BAY60-6583 enhanced DRGN excitability, as demonstrated by increased action potential firing, decreased rheobase and depolarized resting membrane potential and were prevented by PSB-603. Throughout this A2BR-dependent enhancement of neuronal activity, DRGNs could release factors to facilitate myelination processes. Finally, silencing A2BR in DRGNs alone prevents the increased myelination induced by BAY60-6583 in cocultures. In conclusion, our data suggest a different role of A2BR during oligodendrogliogenesis and myelination, depending on their activation on neurons or oligodendroglial cells.