Citations

Abstract Migraine attacks can be provoked in people with underlying primary headache disorders by multiple peripheral mechanisms suggesting the possible convergence of trigeminal nociceptive inputs onto a common, unknown central circuit. As calcitonin gene-related peptide (CGRP) expressing cells in the parabrachial nucleus (PBN) have been implicated in nociplastic pains, we hypothesized that (a) PBN CGRP-expressing neurons and their projections to the central amygdala (CeA) may be an essential central relay of multiple peripheral inputs promoting injury-free migraine headache and (b) this pathway may prioritize threat from activation of cranial afferents over other nociceptive inputs. Periorbital cutaneous allodynia (CA) was determined following supradural application of a cocktail of inflammatory mediators (IM), CGRP or pituitary adenylate cyclase-activating polypeptide (PACAP), or systemic administration of nitroglycerin (NTG) in CalcaCre or wild-type mice. Decreased rearing and photophobia were respectively evaluated as measures of ongoing headache and light-evoked migraine-like pain. Phosphorylation of extracellular signal-regulated kinases (pERK) was evaluated to assess regional neuronal activation. Compared with vehicle, supradural IM increased pERK in the trigeminal nucleus caudalis and PBN, but not in the paraventricular thalamus. Chemogenetic activation (Gq-DREADD) of PBN CGRP neurons elicited CA and photophobia while decreasing rearing. Lesioning of PBN neurons with ibotenic acid suppressed CA produced by supradural IM. Chemogenetic silencing (Gi-DREADD) or expression of tetanus toxin (TeNT) in PBN Calca neurons to prevent neurotransmitter release also inhibited CA elicited by supradural IM, CGRP, PACAP or systemic NTG. CRISPR/Cas9 editing of CeA receptor-associated membrane protein-1 (Ramp1) prevented IM-induced migraine-like symptoms revealing CGRP/CGRP-receptor activation from PBN→CeA projections. In contrast, PBN lesions, chemogenetic manipulation, and TeNT expression in PBN Calca cells and CeA Ramp1 CRISPR/Cas9 editing did not affect acute pain responses induced by hind paw IM injection, intraperitoneal acetic acid, or acute nociceptive behaviors from IM stimulation of the maxillary (V2) and mandibular (V3) branches of the trigeminal nerve. These data reveal a central pathway composed of PBN Calca neurons and CeA CGRP receptor signaling that is both sufficient to elicit migraine-like pain in naive mice and necessary to promote migraine-like pain following activation of the ophthalmic (V1) branch of the trigeminal nerve. Importantly, this pathway is essential for acute pain arising from V1 trigeminal, but dispensable for acute stimuli from other nociceptive afferents. The prioritization of V1 acute nociception suggests evolutionary importance for detecting threats to the head to promote survival through advantageous behaviors such as defensive coping observed in migraine.

Background. Patients having hip fracture surgery are at high risk for postoperative delirium. Red blood cell (RBC) transfusion may increase postoperative delirium risk by causing neuroinflammation. We hypothesized that RBC transfusion would be associated with postoperative delirium in patients having hip fracture surgery. Methods. An observational cohort study was performed using the United States National Surgical Quality Improvement Program (NSQIP) participant use files for hip fracture from 2016 to 2018. Propensity score analysis and inverse probability of treatment weighting (IPTW) were used to reduce bias from confounding. An IPTW adjusted odds ratio for developing postoperative delirium was calculated for patients who received RBC transfusion during surgery or in the 72 hours after. Results. There were 20,838 patients who had eligible current procedural terminology (CPT) codes for primary hip fracture surgery and complete study data. After employing strict exclusions to balance covariates and reduce bias, 3,715 patients remained in the IPTW cohort. Of these, 626 patients (16.9%) received RBC transfusion and 665 patients (17.9%) developed postoperative delirium. IPTW adjustment led to good covariate balance between patients who received RBC transfusion and those who did not. Patients who received RBC transfusion had significantly higher odds of postoperative delirium, IPTW adjusted odds ratio = 1.21, 95% CI = 1.03 to 1.43, andP = 0.02. Discharge location also differed significantly between patients who received RBC transfusion and those who did not (P < 0.001) with in-hospital mortality or referral to hospice occurring in 1.6% of patients who received RBC transfusion and 1.3% of patients who were not transfused. Conclusion. RBC transfusion is associated with increased odds of postoperative delirium after hip fracture surgery and may be associated with worse clinical outcome.

AbstractBackgroundAnemia is associated with poor outcome after major joint replacement surgery, but it is unclear whether sex and race modify its impact on outcome. We hypothesized that anemia would be associated with increased morbidity or mortality after knee arthroplasty surgery and that sex and race would be effect modifiers for this relationship.Study Design and MethodsWe performed a retrospective cohort study of elective knee arthroplasty patients between 2013 and 2018 using data from the National Surgical Quality Improvement Program. Morbidity or mortality after surgery was compared between patients without anemia, with mild anemia, and with moderate to severe anemia. Multivariable logistic regression was used to determine adjusted odds for morbidity or mortality with anemia. Interaction terms were entered into the model to test for effect modification by sex and race.Results243 491 patients were included and 30 135 patients (12.4%) were anemic. Morbidity or mortality occurred in 3.7% of patients without anemia, 5.2% of patients with mild anemia, and 7.1% of patients with moderate to severe anemia (P < .001). After adjustment for confounding variables, mild anemia OR = 1.36 (95% CI = 1.28‐1.45), and moderate to severe anemia OR = 1.92 (95% CI = 1.72‐2.13) were associated with increased odds of morbidity or mortality. Sex, but not race, was a significant effect modifier with men having a greater increase in morbidity or mortality when anemic (P = .02).ConclusionsAnemia is associated with increased morbidity or mortality after knee arthroplasty surgery and men have a greater increase in perioperative risk than women when anemic.