Statistical modeling of acute and chronic pain patient-reported outcomes obtained from ecological momentary assessment.

ABSTRACT: Ecological momentary assessment (EMA) allows for the collection of participant-reported outcomes (PROs), including pain, in the normal environment at high resolution and with reduced recall bias. Ecological momentary assessment is an important component in studies of pain, providing detailed information about the frequency, intensity, and degree of interference of individuals' pain. However, there is no universally agreed on standard for summarizing pain measures from repeated PRO assessment using EMA into a single, clinically meaningful measure of pain. Here, we quantify the accuracy of summaries (eg, mean and median) of pain outcomes obtained from EMA and the effect of thresholding these summaries to obtain binary clinical end points of chronic pain status (yes/no). Data applications and simulations indicate that binarizing empirical estimators (eg, sample mean, random intercept linear mixed model) can perform well. However, linear mixed-effect modeling estimators that account for the nonlinear relationship between average and variability of pain scores perform better for quantifying the true average pain and reduce estimation error by up to 50%, with larger improvements for individuals with more variable pain scores. We also show that binarizing pain scores (eg, <3 and ≥3) can lead to a substantial loss of statistical power (40%-50%). Thus, when examining pain outcomes using EMA, the use of linear mixed models using the entire scale (0-10) is superior to splitting the outcomes into 2 groups (<3 and ≥3) providing greater statistical power and sensitivity.

Evolution of pH-sensitive transcription termination during adaptation to repeated long-term starvation.

Fluctuating environments that consist of regular cycles of co-occurring stress are a common challenge faced by cellular populations. For a population to thrive in constantly changing conditions, an ability to coordinate a rapid cellular response is essential. Here, we identify a mutation conferring an arginine-to-histidine (Arg to His) substitution in the transcription terminator Rho. The rho R109H mutation frequently arose in E. coli populations experimentally evolved under repeated long-term starvation conditions, during which feast and famine result in drastic environmental pH fluctuations. Metagenomic sequencing revealed that populations containing the rho mutation also possess putative loss-of-function mutations in ydcI, which encodes a recently characterized transcription factor associated with pH homeostasis. Genetic reconstructions of these mutations show that the rho allele confers a plastic alkaline-induced reduction of Rho function that, when found in tandem with a ΔydcI allele, leads to intracellular alkalinization and genetic assimilation of Rho mutant function. We further identify Arg to His substitutions at analogous sites in rho alleles from species originating from fluctuating alkaline environments. Our results suggest that Arg to His substitutions in global regulators of gene expression can serve to rapidly coordinate complex responses through pH sensing and shed light on how cellular populations across the tree of life use environmental cues to coordinate rapid responses to complex, fluctuating environments.

Approaches to neuropathic amputation-related pain: narrative review of surgical, interventional, and medical treatments.

BACKGROUND/IMPORTANCE: Neuropathic amputation-related pain can consist of phantom limb pain (PLP), residual limb pain (RLP), or a combination of both pathologies. Estimated of lifetime prevalence of pain and after amputation ranges between 8% and 72%. OBJECTIVE: This narrative review aims to summarize the surgical and non-surgical treatment options for amputation-related neuropathic pain to aid in developing optimized multidisciplinary and multimodal treatment plans that leverage multidisciplinary care. EVIDENCE REVIEW: A search of the English literature using the following keywords was performed: PLP, amputation pain, RLP. Abstract and full-text articles were evaluated for surgical treatments, medical management, regional anesthesia, peripheral block, neuromodulation, spinal cord stimulation, dorsal root ganglia, and peripheral nerve stimulation. FINDINGS: The evidence supporting most if not all interventions for PLP are inconclusive and lack high certainty. Targeted muscle reinnervation and regional peripheral nerve interface are the leading surgical treatment options for reducing neuroma formation and reducing PLP. Non-surgical options include pharmaceutical therapy, regional interventional techniques and behavioral therapies that can benefit certain patients. There is a growing evidence that neuromodulation at the spinal cord or the dorsal root ganglia and/or peripheral nerves can be an adjuvant therapy for PLP. CONCLUSIONS: Multimodal approaches combining pharmacotherapy, surgery and invasive neuromodulation procedures would appear to be the most promising strategy for preventive and treating PLP and RLP. Future efforts should focus on cross-disciplinary education to increase awareness of treatment options exploring best practices for preventing pain at the time of amputation and enhancing treatment of chronic postamputation pain.

Literature review of spinal hematoma case reports: causes and outcomes in pediatric, obstetric, neuraxial and pain medicine cases.

BACKGROUND: The risk of spinal epidural hematoma (SEH) has been described in the literature but the impact in various patient populations has not been assessed in the same study. We identified the risk factors for SEH and calculated the OR for recovery in the pediatric, adult and obstetric (OB) patients based on the degree of neurological deficit before surgery. METHODS: Adult non-OB cases were categorized whether they were on anticoagulants or not; SEH was related to neuraxial or pain procedure; or whether there was adherence to the American Society of Regional Anesthesia (ASRA) guidelines. Eligible cases were identified through PubMed and Embase searches in the English literature from 1954 to July 2022. RESULTS: A total of 940 cases were evaluated. In the pediatric cases, SEH was typically spontaneous, related to coagulopathy or athletic trauma. OB cases were spontaneous or related to neuraxial injections. Among adults on anticoagulant(s), SEH was mostly spontaneous with no related etiology or related to neuraxial procedure. SEH occurred despite adherence to the ASRA guidelines. Among non-OB adults not on anticoagulants, SEH was due to trauma, neuraxial injections, surgery or other causes. Neurological recovery was related to the degree of neurological deficit before surgery. CONCLUSIONS: Our data show a preponderance of spontaneous SEH in all patient populations. SEH developed even though the ASRA guidelines were followed, especially in patients on multiple anticoagulants. Patients with less impairment prior to surgery had a higher likelihood of complete recovery, regardless of the interval between surgery and onset of symptoms.

A Pharmacological Evaluation of the Analgesic Effect and Hippocampal Protein Modulation of the Ketamine Metabolite (2R,6R)-Hydroxynorketamine in Murine Pain Models.

BACKGROUND: The ketamine metabolite (2R,6R)-hydroxynorketamine ([2R,6R]-HNK) has analgesic efficacy in murine models of acute, neuropathic, and chronic pain. The purpose of this study was to evaluate the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) dependence of (2R,6R)-HNK analgesia and protein changes in the hippocampus in murine pain models administered (2R,6R)-HNK or saline. METHODS: All mice were CD-1 IGS outbred mice. Male and female mice underwent plantar incision (PI) (n = 60), spared nerve injury (SNI) (n = 64), or tibial fracture (TF) (n = 40) surgery on the left hind limb. Mechanical allodynia was assessed using calibrated von Frey filaments. Mice were randomized to receive saline, naloxone, or the brain-penetrating AMPA blocker (1,2,3,4-Tetrahydro-6-nitro-2,3-dioxobenzo [f]quinoxaline-7-sulfonamide [NBQX]) before (2R,6R)-HNK 10 mg/kg, and this was repeated for 3 consecutive days. The area under the paw withdrawal threshold by time curve for days 0 to 3 (AUC 0-3d ) was calculated using trapezoidal integration. The AUC 0-3d was converted to percent antiallodynic effect using the baseline and pretreatment values as 0% and 100%. In separate experiments, a single dose of (2R,6R)-HNK 10 mg/kg or saline was administered to naive mice (n = 20) and 2 doses to PI (n = 40), SNI injury (n = 40), or TF (n = 40) mice. Naive mice were tested for ambulation, rearing, and motor strength. Immunoblot studies of the right hippocampal tissue were performed to evaluate the ratios of glutamate ionotropic receptor (AMPA) type subunit 1 (GluA1), glutamate ionotropic receptor (AMPA) type subunit 2 (GluA2), phosphorylated voltage-gated potassium channel 2.1 (p-Kv2.1), phosphorylated-calcium/calmodulin-dependent protein kinase II (p-CaMKII), brain-derived neurotrophic factor (BDNF), phosphorylated protein kinase B (p-AKT), phosphorylated extracellular signal-regulated kinase (p-ERK), CXC chemokine receptor 4 (CXCR4), phosphorylated eukaryotic translation initiation factor 2 subunit 1 (p-EIF2SI), and phosphorylated eukaryotic translation initiation factor 4E (p-EIF4E) to glyceraldehyde 3-phosphate dehydrogenase (GAPDH). RESULTS: No model-specific gender difference in antiallodynic responses before (2R,6R)-HNK administration was observed. The antiallodynic AUC 0-3d of (2R,6R)-HNK was decreased by NBQX but not with pretreatment with naloxone or saline. The adjusted mean (95% confidence interval [CI]) antiallodynic effect of (2R,6R)-HNK in the PI, SNI, and TF models was 40.7% (34.1%-47.3%), 55.1% (48.7%-61.5%), and 54.7% (46.5%-63.0%), greater in the SNI, difference 14.3% (95% CI, 3.1-25.6; P = .007) and TF, difference 13.9% (95% CI, 1.9-26.0; P = .019) compared to the PI model. No effect of (2R,6R)-HNK on ambulation, rearing, or motor coordination was observed. Administration of (2R,6R)-HNK was associated with increased GluA1, GluA2, p-Kv2.1, and p-CaMKII and decreased BDNF ratios in the hippocampus, with model-specific variations in proteins involved in other pain pathways. CONCLUSIONS: (2R,6R)-HNK analgesia is AMPA-dependent, and (2R,6R)-HNK affected glutamate, potassium, calcium, and BDNF pathways in the hippocampus. At 10 mg/kg, (2R,6R)-HNK demonstrated a greater antiallodynic effect in models of chronic compared with acute pain. Protein analysis in the hippocampus suggests that AMPA-dependent alterations in BDNF-TrkB and Kv2.1 pathways may be involved in the antiallodynic effect of (2R,6R)-HNK.

Effects of Adding Intrathecal Epinephrine to Spinal Anesthesia on Anesthesia-Related Cesarean Delivery Outcomes: Should We Reconsider Its Use?

BACKGROUND:  Intrathecal epinephrine is used to increase the duration of spinal anesthesia for amenable surgical procedures anticipated to require additional time; however, in the ambulatory setting, it is associated with a prolonged time to post-anesthesia care unit (PACU) discharge. The current study's authors hypothesized that adding intrathecal epinephrine to spinal anesthesia for cesarean delivery would be associated with a dose-dependent prolonged post-anesthesia unit length of stay. METHODS: A single-center, retrospective study of patients undergoing repeat cesarean delivery under spinal anesthesia from 2011 to 2015 was conducted. Patients received spinal bupivacaine 12 mg, morphine 150 mcg, and fentanyl 15 mcg with no-epinephrine, 100 mcg, or 200 mcg of epinephrine. The primary outcome was recovery room length of stay. Secondary outcomes were surgical duration, intraoperative vasopressor use, perioperative opioids, and antiemetic use. RESULTS:  Data were analyzed for 1,362 patients. Median recovery room stay was 123 min (interquartile range, 100 to 150) and was not different among groups. More women receiving epinephrine 200 mcg had ≥2 prior cesarean deliveries compared with no-epinephrine or 100 mcg. No significant differences in surgical duration or intraoperative opioids were identified among the groups. Median intraoperative vasopressor use was increased by 225 mcg of phenylephrine equivalents (99% CI, 25 mcg to 430 mcg) in the 100 mcg group and 250 mcg of phenylephrine equivalents in the 200 mcg group (99% CI, 75 mcg to 500 mcg) compared to no-epinephrine (P<0.001). Recovery room antiemetic and opioid analgesic administration were not different among groups. CONCLUSIONS:  Based on the results of this study, the addition of intrathecal epinephrine for women undergoing cesarean delivery increases intraoperative vasopressor use but does not prolong PACU length of stay, reduce intraoperative opioids, or increase antiemetic requirements postoperatively. The current study also demonstrated that surgical duration times were not different among the no-epinephrine, 100 mcg, and 200 mcg epinephrine groups.

Association between breakthrough labor pain, patient-controlled epidural analgesia use, and numeracy: A pilot observational study.

OBJECTIVE: Labor analgesia can be maintained with a continuous epidural infusion, supplemented by patient-controlled epidural boluses. patient-controlled epidural boluses use and timing require numeric understanding, as patients need to understand when they can administer supplemental boluses, lockout intervals, and total doses. We hypothesized that women with lower numeric literacy have a higher rate of provider-administered supplemental boluses for breakthrough pain because they do not understand the concept behind patient-controlled epidural boluses. DESIGN: Pilot observational study SETTING: Labor and Delivery Suite PARTICIPANTS: Nulliparous, English-speaking patients with singleton, vertex pregnancies admitted for postdates (gestational age ≥ 41 weeks) induction of labor requesting neuraxial labor analgesia. INTERVENTIONS: Combined spinal-epidural labor analgesia was initiated with intrathecal fentanyl and epidural analgesia was maintained using continuous epidural infusion with patient-controlled epidural boluses. MEASUREMENTS AND FINDINGS: Numeric literacy was assessed using the Lipkus 7-item expanded numeracy test. Patients were stratified by whether or not they required supplemental provider-administered analgesia and patient-controlled epidural boluses use patterns were evaluated. A total of 89 patients completed the study. There were no demographic differences between patients who required supplemental analgesia compared with those who did not. Patients that required supplemental analgesia were more likely to request and receive patient-controlled epidural boluses (P<0.001). Hourly bupivacaine requirement was higher in women with breakthrough pain. There were no differences in numeric literacy between the two groups. KEY CONCLUSIONS: Patients who required treatment of breakthrough pain had higher patient-controlled epidural boluses demands-to-delivery ratio. Numeric literacy was not correlated with the need for provider-administered supplemental boluses. IMPLICATIONS FOR PRACTICE: Easy to understand scripts on how to use patient-controlled epidural boluses allows for understanding of patient-controlled epidural boluses use.

Predicting chronic postsurgical pain: current evidence and a novel program to develop predictive biomarker signatures.

ABSTRACT: Chronic pain affects more than 50 million Americans. Treatments remain inadequate, in large part, because the pathophysiological mechanisms underlying the development of chronic pain remain poorly understood. Pain biomarkers could potentially identify and measure biological pathways and phenotypical expressions that are altered by pain, provide insight into biological treatment targets, and help identify at-risk patients who might benefit from early intervention. Biomarkers are used to diagnose, track, and treat other diseases, but no validated clinical biomarkers exist yet for chronic pain. To address this problem, the National Institutes of Health Common Fund launched the Acute to Chronic Pain Signatures (A2CPS) program to evaluate candidate biomarkers, develop them into biosignatures, and discover novel biomarkers for chronification of pain after surgery. This article discusses candidate biomarkers identified by A2CPS for evaluation, including genomic, proteomic, metabolomic, lipidomic, neuroimaging, psychophysical, psychological, and behavioral measures. Acute to Chronic Pain Signatures will provide the most comprehensive investigation of biomarkers for the transition to chronic postsurgical pain undertaken to date. Data and analytic resources generatedby A2CPS will be shared with the scientific community in hopes that other investigators will extract valuable insights beyond A2CPS's initial findings. This article will review the identified biomarkers and rationale for including them, the current state of the science on biomarkers of the transition from acute to chronic pain, gaps in the literature, and how A2CPS will address these gaps.

Mirror Therapy for the Management of Phantom Limb Pain: A Single- Center Experience.

BACKGROUND: Phantom limb pain (PLP) can have devastating consequences, affecting up to 90% of amputees. PLP is associated with analgesia dependence and impaired quality of life. Mirror therapy (MT) is a novel treatment that has been applied in other pain syndromes. We prospectively evaluated MT in the management of PLP. METHODS: A prospective study of patients recruited between 2008 and 2020 who underwent unilateral major limb amputation, with a healthy contralateral limb. Participants were invited to attend weekly MT sessions. Pain in the 7 days prior to each MT session was scored on a Visual Analog Scale (VAS: 0-10 mm) and the short form McGill pain questionnaire. RESULTS: Ninety eight patients (68 males and 30 females) aged 17-89 years were recruited over 12 years. Forty four percent of patients had amputations due to peripheral vascular disease. Over an average of 2.5 sessions, the final treatment score on the VAS scale was 2.6 (standard deviation ± 3.0) with a reduction of 4.5 points on VAS score. As a comparison using the short form McGill pain questionnaire scoring system, the average final treatment score was 3.2 (± 5.0) with 91% overall improvement. CONCLUSIONS: MT is a very powerful and effective intervention for PLP. It is an exciting addition to the armory of vascular surgeons in the management of this condition.

Case Studies in the Assessment of Microbial Fitness: Seemingly Subtle Changes Can Have Major Effects on Phenotypic Outcomes.

Following the completion of an adaptive evolution experiment, fitness evaluations are routinely conducted to assess the magnitude of adaptation. In doing so, proper consideration should be given when determining the appropriate methods as trade-offs may exist between accuracy and throughput. Here, we present three instances in which small changes in the framework or execution of fitness evaluations significantly impacted the outcomes. The first case illustrates that discrepancies in fitness conclusions can arise depending on the approach to evaluating fitness, the culture vessel used, and the sampling method. The second case reveals that variations in environmental conditions can occur associated with culture vessel material. Specifically, these subtle changes can greatly affect microbial physiology leading to changes in the culture pH and distorting fitness measurements. Finally, the last case reports that heterogeneity in CFU formation time can result in inaccurate fitness conclusions. Based on each case, considerations and recommendations are presented for future adaptive evolution experiments.

Effects of intra-articular injection of an acellular equine liquid amniotic allograft in healthy equine joints.

OBJECTIVE: Evaluate effects of acellular equine liquid amnion allograft (ELAA) injected into healthy equine joints. STUDY DESIGN: Randomized, blinded, controlled experiment. ANIMALS: Eight healthy adult horses. METHODS: One intercarpal joint (ICJ) of each horse was randomly assigned to be injected with 1.5 ml of ELAA (treatment) while the contralateral ICJ was injected with 1.5 ml of 0.9% NaCl (control). Subjective lameness evaluation, force plate analysis, and synovial fluid analysis, including interleukin-1 receptor antagonist (IL-1ra) analysis, were performed before (day 0) and at days 1, 3, 5, and 10. Synovial fluid analysis was also performed on days 20 and 30. RESULTS: No difference in subjective lameness (P = .75) and no decrease in peak vertical force or vertical impulse were seen in any limb on any day. Total nucleated cell count (TNCC) was increased in treatment joints on days 1 (P = .0007; T: 6039 cells/µl, C: 240 cells/µl) and 3 (P < .0001; T: 1119 cells/µl, C: 240 cells/µl). Log-10 transformed values for IL-1ra were higher in treated joints on days 1 (P = .0005; T: 3553.7 pg/ml, C: 1890.1 pg/ml) and 3 (P = .01; T: 2283.2 pg/ml, C: 1250.7 pg/ml). CONCLUSION: Injection of ELAA into the ICJ caused an increase in synovial fluid TNCC in comparison with saline control but no lameness was observed. There was increased IL-1ra on days 1 and 3 after ELAA injection. CLINICAL SIGNIFICANCE: Intra-articular injection of ELAA into healthy equine joints results in no significant safety concerns. The observed increase in IL-1ra may provide beneficial effects in inflamed joints.

Efficacy and Safety of Cervical and High-Thoracic Dorsal Root Ganglion Stimulation Therapy for Complex Regional Pain Syndrome of the Upper Extremities.

OBJECTIVES: The purpose of this study was to evaluate analgesic and safety considerations for high thoracic and cervical dorsal root ganglion (DRG) neuromodulation for complex regional pain syndrome (CRPS). We hypothesized that DRG neuromodulation would provide sustained analgesia with complications like that of low thoracic or lumbar electrode implantation. MATERIALS AND METHODS: A single-center, retrospective study was conducted of patients with CRPS I or II of the upper extremities, refractory to previous therapies, who were treated with DRG neuromodulation in the upper thoracic and cervical spine. The primary outcome was successful DRG therapy, defined as ≥ 50% pain relief on a Numeric Rating Scale (NRS) 0 to 10 pain scale at six months after implantation. A secondary outcome was a reduction in daily opioid use after DRG therapy. RESULTS: After a DRG stimulation trial, 17 of 20 patients (85%) had ≥ 50% improvement in NRS pain and underwent a permanent pulse generator implant, with 100% endorsing ≥ 50% pain relief at six months. Mean NRS pain scores before DRG neuromodulation were 9.3 ± 1.1, with a mean reduction of 5.5 (95% CI, 4.5-6.6; p < 0.001) at six months. Ten patients were taking opioids at baseline; the median (interquartile range) dose was 45 mg (23 to 120) morphine equivalents (MME), which was reduced to 20 MME (15 to 40) at six months. The median reduction in daily MME use was -25 (95% CI, -100 to 20; p = 0.099). Six of 20 patients (30%) experienced a complication: three had lead migration; two experienced paresthesias; and one had a reduction in shoulder mobility. One patient had symptoms of a reversible spinal cord compression immediately after implant, requiring emergent electrode removal. CONCLUSIONS: DRG neuromodulation for patients with CRPS of the upper extremities produced clinically important analgesia and reduced opioid use for ≥ six months but was associated with one serious complication.

Early incident and subsyndromal delirium in older patients undergoing elective surgical procedures: a randomized clinical trial of an avoid delirium protocol.

Background: Pharmacological avoidance guidelines for preventing delirium have been suggested; however, there are limited pragmatic studies of these strategies. Early (<24 h) delirium can be observed in the postoperative care unit and is associated with an increased risk of subsequent delirium. We examined the effectiveness of an avoid delirium protocol (ADP) in older (>65 years) patients undergoing elective surgeries. Methods: The randomized controlled trial assessed an ADP developed using the American Geriatric Society's Clinical Practice Guidelines for Postoperative Delirium in Older Adults, on early (<24 h) incident or subsyndromal delirium. Delirium was assessed using the confusion assessment method before surgery, in the post-anesthesia care unit, and on postoperative day 1. The primary outcome of early delirium was the combined incidence of incident or subsyndromal delirium. Results: Early delirium was identified in 24/235 patients (10.2%) with a risk ratio of 1.27 (95% CI 0.59-2.73, P = 0.667) for patients randomized to the ADP. In cases with protocol adherence and no benzodiazepine use, early delirium was present in 10/ 73 (13.7%) compared to 14/148 (9.5%) in non-adherent cases [risk ratio 1.45 (95% CI 0.57-3.10, P = 0.362)]. Lower American Society of Anesthesiologists physical class [odds ratio 3.31 (95% CI 1.35-8.92, P = 0.008)] and an inpatient admission [odds ratio 2.67 (95% CI 1.55-4.87, P = 0.0002)] were associated with early delirium. Conclusions: Our findings suggest that pharmacological avoidance protocols limiting or avoiding the use of specific classes of medications are not effective in reducing early incident or subsyndromal delirium in older patients undergoing elective surgery.

Sine-limiting microcell solar concentrators for space.

Microcell concentrating photovoltaics (µCPV) have the potential to improve performance and reduce the cost of solar power in space. Here, we introduce an ultracompact V-cone tailored edge ray (V-TERC) concentrator, rooted in nonimaging optics, which enables operation near the sine limit. Relative to previous space µCPV implementations, this concentrator design enables an approximate four-fold increase in concentration ratio for a given acceptance angle and specific power. We validate the design through ray tracing simulations and construction of a proof-of-concept system that consists of a 650 × 650 µm2 triple-junction microcell bonded to a 3.1 mm-thick prototype V-TERC optic. In outdoor testing on a sunny day, the system achieves a power conversion efficiency of 30% at a geometric gain of 137× with a specific power of 90 W kg-1 and an acceptance angle of ±4.5°. This is a record combination for µCPV to date and represents an important step toward increasing efficiency and lowering the cost of solar power in space.

Analgesic Effectiveness and Dorsal Root Ganglia Protein Modulation of a Peripheral Adenosine Monophosphate Kinase Alpha Activator (O304) Following Lumbar Disk Puncture in the Mouse.

BACKGROUND: Disk herniation is a primary cause of radicular back pain. The purpose of this study was to evaluate the antiallodynic effective dose in 50% of the sample (ED 50 ) and dorsal root ganglion (DRG) protein modulation of a peripheral direct adenosine monophosphate kinase alpha (AMPKα) activator (O304) in a murine model of lumbar disk puncture. METHODS: Male (n = 28) and female (n = 28) mice (C57BL6/J) were assessed for hind paw withdrawal threshold (PWT) and burrowing. Abdominal surgery was performed on all mice, and 48 received a lumbar disk puncture (27-G needle), with 8 serving as nondisk puncture controls. Assessments were repeated at day 7, and mice were then randomized into 5 groups of equal numbers of males and females: O304 at 100 mg/kg (n = 10), 150 mg/kg (n = 10), 200 mg/kg (n = 10), and 250 mg/kg (n = 10) or drug vehicle (n = 8). Starting on day 7, mice received daily gavages of O304 or vehicle for 7 days. On days 14 and 21 PWT and on day 14 burrowing were assessed. The area under the PWT by time curve (AUC) from day 7 to 21 was determined by trapezoidal integration. DRG protein modulation was evaluated in male (n = 10) and female (n = 10) mice (C57BL6/J). Following disk puncture, mice were randomized to receive O304 200 mg/kg or vehicle for 7 days starting on day 7. On day 14, mice were euthanized; the DRG harvested and immunoblot performed for mammalian target of rapamycin (mTOR), transient receptor potential ankyrin 1 (TRPA1), phosphorylated adenosine monophosphate kinase (p-AMPK), phosphorylated extracellular signal-regulated kinase (p-ERK), phosphorylated eukaryotic translation initiation factor 2 subunit 1 (p-EIF2S1), phosphorylated eukaryotic translation initiation factor 4e (p-EIF4E), and glyceraldehyde 3-phosphate dehydrogenase (GADPH). RESULTS: Disk puncture decreased PWT greater in female mice compared with male mice and decreased burrowing at 7 days. PWTs were increased with increasing doses of O304 from 150 to 250 mg/g on day 14 and sustained through day 21. The ED 50 (95% confidence interval [CI]) for reducing mechanical allodynia was 140 (118-164) mg/kg. Burrowing was not increased at day 14 compared to day 7 by O304 administration. Compared to vehicle-treated animals, O304 increased (95% CI) the p-AMPK/GADPH ratio, difference 0.27 (0.08-0.45; P = . 004) and decreased (95% CI) the ratios of p-TRPA1, p-ERK1/2, pEIF4E, and p-EIF2S1 to GADPH by -0.49 (-0.61 to -0.37; P < . 001), -0.53 (-0.76 to -0.29; P < . 001), -0.27 (-0.42 to 0.11; P = . 001), and -0.21 (-0.32 to -0.08; P = . 003) in the DRG, respectively. CONCLUSIONS: The direct peripheral AMPK activator O304 reduced allodynia in a dose-dependent manner, and immunoblot studies of the DRG showed that O304 increased p-AMPK and decreased TRPA1, p-ERK1/2, as well as translation factors involved in neuroplasticity. Our findings confirm the role of peripheral AMPKα activation in modulating nociceptive pain.

The effects of sex and neuter status on trauma survival in dogs: A Veterinary Committee on Trauma registry study.

OBJECTIVE: To determine the effect of sex and neuter status on trauma survival in dogs. DESIGN: Multi-institutional prospective case series, September 2013 to March 2019, retrospectively analyzed. SETTING: Level I and II Veterinary Trauma Centers. ANIMALS: Consecutive sample of 2649 dogs in the American College of Veterinary Emergency and Critical Care Veterinary Committee on Trauma patient registry meeting inclusion criteria. For inclusion, dogs had to have complete data entries, be postpubertal (≥7 months age in females and ≥10 months age in males), and have sustained moderate to severe trauma (animal trauma triage [ATT] score ≥5/18). Dogs that were dead upon arrival, euthanized for financial or unknown reasons alone, or that were presented by a Good Samaritan but subsequently humanely euthanized were excluded. MEASUREMENTS AND MAIN RESULTS: Data collected included age, sex, neuter status (intact, neutered), trauma type (blunt, penetrating, both), outcome (survived to hospital discharge, died, euthanized), and reason for euthanasia (grave prognosis, financial reasons, or both). Of 2649 eligible dogs, 56% survived to hospital discharge (n = 1469). Neutered females had a significantly higher survival rate (58.3% vs 51.3%; P = 0.03) compared to intact females, and neutered males had a significantly higher survival rate (56.6% vs 50.7%; P = 0.04) compared to intact males. There was no significant difference in survival between intact females and intact males (P = 0.87) or between neutered females and neutered males (P = 0.46). Mean cumulative ATT score was higher in intact groups and was found to be a significant predictor of survival (P < 0.01). Based on logistic models, overall odds of survival were 20.7% greater in neutered dogs. CONCLUSIONS: Gonadectomy is associated with lower ATT scores and improved survival after moderate to severe trauma in both female and male dogs.

Multi-Site Observational Study to Assess Biomarkers for Susceptibility or Resilience to Chronic Pain: The Acute to Chronic Pain Signatures (A2CPS) Study Protocol.

Chronic pain has become a global health problem contributing to years lived with disability and reduced quality of life. Advances in the clinical management of chronic pain have been limited due to incomplete understanding of the multiple risk factors and molecular mechanisms that contribute to the development of chronic pain. The Acute to Chronic Pain Signatures (A2CPS) Program aims to characterize the predictive nature of biomarkers (brain imaging, high-throughput molecular screening techniques, or "omics," quantitative sensory testing, patient-reported outcome assessments and functional assessments) to identify individuals who will develop chronic pain following surgical intervention. The A2CPS is a multisite observational study investigating biomarkers and collective biosignatures (a combination of several individual biomarkers) that predict susceptibility or resilience to the development of chronic pain following knee arthroplasty and thoracic surgery. This manuscript provides an overview of data collection methods and procedures designed to standardize data collection across multiple clinical sites and institutions. Pain-related biomarkers are evaluated before surgery and up to 3 months after surgery for use as predictors of patient reported outcomes 6 months after surgery. The dataset from this prospective observational study will be available for researchers internal and external to the A2CPS Consortium to advance understanding of the transition from acute to chronic postsurgical pain.

Patient and operative factors associated with unanticipated intensive care admission and outcomes following posterior fossa decompressions in children: A retrospective study.

INTRODUCTION: Posterior fossa decompression for Chiari I Malformation is a common pediatric neurosurgical procedure. We sought to identify the impact of anesthesia-related intraoperative complications on unanticipated admission to the intensive care unit and outcomes following posterior fossa decompression. METHODS: Medical records of all patients <18 years who underwent surgery for Chiari I malformation between 1/1/09 and 1/31/21 at the Ann & Robert H. Lurie Children's Hospital of Chicago were included. Records were reviewed for patient characteristics, anesthesia-related intraoperative complications, postoperative complications, and surgical outcomes. The primary outcome was the incidence of unanticipated admission to the intensive care unit, and the primary variable of interest was an anesthesia-related intraoperative complication. Patient, surgical characteristics, and year of surgery were also compared between patients with and without an unanticipated admission to the intensive care unit, and a multi-variable adjusted estimate of odds of unanticipated admission to the intensive care unit admission following an anesthesia-related intraoperative complication was performed. Secondary outcomes included anesthesia factors associated with an anesthesia-related intraoperative event, and postoperative complications and surgical outcomes between patients admitted to the intensive care unit and those who were not. RESULTS: Two hundred ninety-six patients with Chiari I Malformation were identified. Clinical characteristics associated with an unanticipated admission to the intensive care unit were younger age, American Society of Anesthesiologist (ASA) physical status >2 and an anesthesia-related intraoperative complication. 29 anesthesia-related intraoperative complications were observed in 25 patients (8.4%). Two of 25 patients (8%) with an anesthesia-related intraoperative complication compared with 3 of 271 (1%) patients without anesthesia-related intraoperative complication had an unanticipated admission to the intensive care unit, odds ratio 7.8 (95% CI 1.2-48.8, p = .010). When adjusted for age, sex, ASA physical status, presenting symptoms, concomitant syringomyelia, previous decompression surgery and year of surgery, the odds ratio for an unanticipated admission to the intensive care unit following an anesthesia-related intraoperative complication was 5.9 (95% CI 0.51-59.6, p = .149). There were no differences in surgical outcomes between patients with or without an unanticipated admission to the intensive care unit. CONCLUSION: Our study demonstrates that although anesthesia-related intraoperative complications during posterior fossa decompression are infrequent, they are associated with an increased risk of an unanticipated admission to the intensive care unit.