Correction: Reduced prefrontal cortex and sympathetic nervous system activity correlate with fatigue after aHSCT
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Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis and neuromyelitis optica spectrum disorder — recommendations from ECTRIMS and the EBMT
Autologous haematopoietic stem cell transplantation (AHSCT) is a treatment option for relapsing forms of multiple sclerosis (MS) that are refractory to disease-modifying therapy (DMT). AHSCT after failure of high-efficacy DMT in aggressive forms of relapsing–remitting MS is a generally accepted indication, yet the optimal placement of this approach in the treatment sequence is not universally agreed upon. Uncertainties also remain with respect to other indications, such as in rapidly evolving, severe, treatment-naive MS, progressive MS, and neuromyelitis optica spectrum disorder (NMOSD). Furthermore, treatment and monitoring protocols, rehabilitation and other supportive care before and after AHSCT need to be optimized. To address these issues, we convened a European Committee for Treatment and Research in Multiple Sclerosis Focused Workshop in partnership with the European Society for Blood and Marrow Transplantation Autoimmune Diseases Working Party, in which evidence and key questions were presented and discussed by experts in these diseases and in AHSCT. Based on the workshop output and subsequent written interactions, this Consensus Statement provides practical guidance and recommendations on the use of AHSCT in MS and NMOSD. Recommendations are based on the available evidence, or on consensus when evidence was insufficient. We summarize the key evidence, report the final recommendations, and identify areas for further research.
Inhibition of sympathetic tone via hypothalamic descending pathway propagates glucocorticoid-induced endothelial impairment and osteonecrosis of the femoral head
Osteonecrosis of the femoral head (ONFH) is a common complication of glucocorticoid (GC) therapy. Recent advances demonstrate that sympathetic nerves regulate bone homeostasis, and GCs lower the sympathetic tone. Here, we show that the dramatically decreased sympathetic tone is closely associated with the pathogenesis of GC-induced ONFH. GCs activate the glucocorticoid receptor (GR) but hinder the activation of the mineralocorticoid receptor (MR) on neurons in the hypothalamic paraventricular nucleus (PVN). This disrupts the balance of corticosteroid receptors (GR/MR) and subsequently reduces the sympathetic outflow in the PVN. Vascular endothelial cells rapidly react to inhibition of sympathetic tone by provoking endothelial apoptosis in adult male mice treated with methylprednisolone (MPS) daily for 3 days, and we find substantially reduced H-type vessels in the femoral heads of MPS-treated ONFH mice. Importantly, treatment with a GR inhibitor (RU486) in the PVN promotes the activation of MR and rebalances the ratio of GR and MR, thus effectively boosting sympathetic outflow, as shown by an increase in tyrosine hydroxylase expression in both the PVN and the sympathetic postganglionic neurons and an increase in norepinephrine levels in both the serum and bone marrow of the femoral head of MPS-treated mice. Rebalancing the corticosteroid receptors mitigates GC-induced endothelial impairment and ONFH and promotes angiogenesis coupled with osteogenesis in the femoral head, while these effects are abolished by chemical sympathectomy with 6-OHDA or adrenergic receptor-β2 (Adrb2) knockout. Furthermore, activating Adrb2 signaling in vivo is sufficient to rescue the GC-induced ONFH phenotype. Mechanistically, norepinephrine increases the expression of the key glycolytic gene 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) via Adrb2-cyclic AMP response element-binding protein (CREB) signaling. Endothelial-specific overexpression of PFKFB3 attenuates endothelial impairment and prevents severe osteonecrosis in MPS-treated Adrb2 knockout mice. Thus, GC inhibits sympathetic tone via the hypothalamic descending pathway, which, in turn, acts as a mediator of GC-induced ONFH.
Effect of regional crosstalk between sympathetic nerves and sensory nerves on temporomandibular joint osteoarthritic pain
Temporomandibular joint osteoarthritis (TMJ-OA) is a common disease often accompanied by pain, seriously affecting physical and mental health of patients. Abnormal innervation at the osteochondral junction has been considered as a predominant origin of arthralgia, while the specific mechanism mediating pain remains unclear. To investigate the underlying mechanism of TMJ-OA pain, an abnormal joint loading model was used to induce TMJ-OA pain. We found that during the development of TMJ-OA, the increased innervation of sympathetic nerve of subchondral bone precedes that of sensory nerves. Furthermore, these two types of nerves are spatially closely associated. Additionally, it was discovered that activation of sympathetic neural signals promotes osteoarthritic pain in mice, whereas blocking these signals effectively alleviates pain. In vitro experiments also confirmed that norepinephrine released by sympathetic neurons promotes the activation and axonal growth of sensory neurons. Moreover, we also discovered that through releasing norepinephrine, regional sympathetic nerves of subchondral bone were found to regulate growth and activation of local sensory nerves synergistically with other pain regulators. This study identified the role of regional sympathetic nerves in mediating pain in TMJ-OA. It sheds light on a new mechanism of abnormal innervation at the osteochondral junction and the regional crosstalk between peripheral nerves, providing a potential target for treating TMJ-OA pain.
A systematic review of digital and imaging technologies for measuring fatigue in immune mediated inflammatory diseases
Chronic fatigue greatly impacts the quality of life in individuals with immune-mediated inflammatory disease (IMID). Currently, fatigue assessment relies on patient-reported outcome (PRO) questionnaires. A systematic review following PRISMA guidelines was conducted to explore how digital and imaging technologies have been used to measure fatigue. PubMed and Cochrane Library were searched from 2003 to June 2023. Study quality was assessed using the STROBE checklist for observational studies. The database search identified 1541 studies; 16 were selected for inclusion, including three clinical trial reports. Disease cohorts included in this review were rheumatoid arthritis, primary Sjögren’s syndrome, systemic lupus erythematosus, and inflammatory bowel disease. The majority of the studies found significant associations between fatigue, as assessed by PROs, and various digital and imaging endpoints. However, the studies were limited by a small sample size and short duration. This review stresses the need for additional research on fatigue using innovative digital and imaging modalities.
No evidence for decision fatigue using large-scale field data from healthcare
Decision fatigue is the idea that making decisions is mentally demanding and eventually leads to deteriorated decision quality. Many studies report results that appear consistent with decision fatigue. However, most of this evidence comes from observed sequential patterns using retrospective designs, without preregistration or external validation and with low precision in how decision fatigue is operationalized. Here we conducted an empirical test of decision fatigue using large-scale, high-resolution data on healthcare professionals’ medical judgments at a national telephone triage and medical advice service. This is a suitable setting for testing decision fatigue because the work is both hard and repetitive, yet qualified, and the variation in scheduling produced a setting where level of fatigue could be regarded as near random for some segments of the data. We hypothesized increased use of heuristics, more specifically convergence toward personal defaults in case judgments, and higher assigned urgency ratings with fatigue. We tested these hypotheses using one-sided Bayes Factors computed from underlying Bayesian generalized mixed models with random intercepts. The results consistently showed relative support for the statistical null hypothesis of no difference in decision-making depending on fatigue (BF0+ > 22 for all main tests). We thus found no evidence for decision fatigue. Whereas these results don’t preclude the existence of a weaker or more nuanced version of decision fatigue or more context-specific effects, they cast serious doubt on the empirical relevance of decision fatigue as a domain general effect for sequential decisions in healthcare and elsewhere.
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