Evaluating residual anti-Xa levels following discontinuation of treatment-dose enoxaparin in patients presenting for elective surgery: a prospective observational trial.

INTRODUCTION: Prior studies have demonstrated that patients presenting for elective surgery may have higher-than-expected residual anti-Xa level activity at or beyond 24 hours following their last treatment dose of enoxaparin. Given that 24 hours of abstinence is currently recommended by both European and American societies before the performance of neuraxial or deep anesthetic/analgesic procedures, determining the actual timeframe at which residual anti-Xa level activity reliably falls below 0.2 IU/mL, the lower limit of the target range for thromboprophylaxis, is critical. METHODS: This was a prospective observational trial. Consenting patients on treatment-dose enoxaparin were randomized to either a 24-hour group (last dose at 07:00 the day prior to surgery) or a 36-hour group (last dose at 19:00 2 days prior to surgery). On arrival for surgery, blood samples were obtained to assess residual anti-Xa level activity and renal function. The primary outcome was residual anti-Xa level activity following the last treatment dose of enoxaparin. Incorporating all patients, linear regression modeling was performed to predict the timepoint at which the level of anti-Xa activity reliably fell below 0.2 IU/mL. RESULTS: 103 patients were analyzed. Time from the last dose at which residual anti-Xa activity fell below 0.2 IU/mL, based on the upper bound of the 95% CI, was 31.5 hours. No correlation overall between age, renal function, or sex was found. CONCLUSION: Residual levels of anti-Xa activity do not reliably fall below 0.2 IU/mL 24 hours following discontinuation of treatment-dose enoxaparin. Therefore, current time-based guidelines are not conservative enough. Routine anti-Xa testing should be strongly considered, or current time-based guidelines should be reassessed. TRIAL REGISTRATION NUMBER: NCT03296033.

An investigation of the use of ethyl chloride and meloxicam to decrease the pain associated with a single or double incision method of castration in piglets.

Castration is a stressful and painful procedure that can impact swine welfare negatively. The objectives of this study were to (1) evaluate the effect of one incision compared to two incisions and the use of a topical vapocoolant (VAPO; ethyl chloride; a topical anesthetic) applied before castration and (2) evaluate the most effective combination in reducing pain in objective 1 and the use of Metacam®; meloxicam before castration on measures of performance, behavior, and physiology. Study 1 consisted of six treatment groups (N = 27 pigs per treatment) and included: nothing (NO); sham castrated (SH); one incision castration (C1); one incision castration plus VAPO (C1V); two incision castration (C2); two incision castration plus VAPO (C2V). Body weights and blood samples were taken at baseline and other time points after castration. Behavior measures were collected for 24 h after castration. Wound scores were collected daily for 10 days. The C1 pigs and C1V pigs were significantly heavier than the other castrated treatment groups but not different from NO and SH pigs. Vocalizations were louder for C1 and C1V pigs (P = 0.0015). Study 2 (N = 40 pigs per treatment) included: nothing (NO); one incision castration (C1); and one incision castration plus meloxicam administered 15 min before castration (C1M). The same measures (performance, behavior, and physiology) were collected as in Study 1. Performance measures and behavior did not differ among treatment groups. Physiological measures were only different for red blood cells (RBC; P = 0.0304). Pigs in C1 and C1M treatment groups had cortisol concentrations that were greater than the NO treatment group at 15 min post-castration (P < 0.05). The data collected give insight into the benefits of one-incision castration compared to 2-incision castration. However, the data only support a lower-level relief from acute pain associated with castration, as it is evident that pigs still experience stress at 15 min post-castration with or without the use of meloxicam. Further research could potentially identify the correct timing, route and dose for the administration of meloxicam.

Patterns in emergency department unscheduled return visits during the COVID-19 pandemic.

INTRODUCTION: Fear surrounding nosocomial infections, expanded telehealth, and decreases in ED (emergency department) utilization altered the way patients sought emergency care during the COVID pandemic. This study aims to evaluate COVID-19's impact on the frequency and characteristics of unscheduled return visits (URVs) to the adult and pediatric ED. METHODS: In this retrospective cohort study, the electronic medical record was used to identify ≤9-day URVs at a tertiary adult and pediatric ED from 4/16/19-2/29/20 (control) and 4/16/20-2/28/21 (COVID). The primary outcome, proportion of total ED visits made up by URVs, and secondary outcomes, patient characteristics (age), illness acuity (emergency severity index (ESI)), disposition, and mortality were compared between the cohorts. Pediatric and adult data were analyzed separately. A sub-analysis was performed to exclude patients with suspected respiratory infections. RESULTS: For adults, n = 4265, there was no significant difference between the proportion of ED census made up by URVs (4.56% (control) vs 4.76% (COVID), p = 0.17), mean patient age (46.33 (control) vs 46.18 (COVID), p = 0.80), ESI acuity (2.95 (control) vs 2.95 (COVID), p = 0.83), disposition (admission 0.32% (control) vs 0.39% (COVID), p = 0.69), and mortality (0.23% (control) and 0.49% (COVID), p = 0.15). When excluding possible respiratory infections comparisons remained insignificant. For pediatrics, n = 1214, there was a significant difference in the proportion of ED census made up by URVs (4.83% (control) to 3.55% (COVID), p < 0.01), age (5.52 (control) vs 6.43 (COVID), p = 0.01), and ESI acuity (3.31 (control) vs 3.17 (COVID), p < 0.01). There was no difference in disposition (admission 0.12% (control) vs 0% (COVID), p = 1). When excluding possible respiratory infections acuity (p = 0.03) remained significant. CONCLUSION: In the adult population, COVID did not significantly alter any of our outcomes. For pediatric patients, a decrease in the proportion of URVs and increase in acuity during COVID suggests that patients may have had other means of accessing care, avoided the ED, received more adequate care at initial presentation, or represented when more acutely ill.

Thiamine Supplementation in Patients With Alcohol Use Disorder Presenting With Acute Critical Illness : A Nationwide Retrospective Observational Study.

BACKGROUND: Thiamine supplementation is recommended for patients with alcohol use disorder (AUD). The authors hypothesize that critically ill patients with AUD are commonly not given thiamine supplementation. OBJECTIVE: To describe thiamine supplementation incidence in patients with AUD and various critical illnesses (alcohol withdrawal, septic shock, traumatic brain injury [TBI], and diabetic ketoacidosis [DKA]) in the United States. DESIGN: Retrospective observational study. SETTING: Cerner Health Facts database. PATIENTS: Adult patients with a diagnosis of AUD who were admitted to the intensive care unit with alcohol withdrawal, septic shock, TBI, or DKA between 2010 and 2017. MEASUREMENTS: Incidence and predicted probability of thiamine supplementation in alcohol withdrawal and other critical illnesses. RESULTS: The study included 14 998 patients with AUD. Mean age was 52.2 years, 77% of participants were male, and in-hospital mortality was 9%. Overall, 7689 patients (51%) received thiamine supplementation. The incidence of thiamine supplementation was 59% for alcohol withdrawal, 26% for septic shock, 41% for TBI, and 24% for DKA. Most of those receiving thiamine (n = 3957 [52%]) received it within 12 hours of presentation in the emergency department. The predominant route of thiamine administration was enteral (n = 3119 [41%]). LIMITATION: Specific dosing and duration were not completely captured. CONCLUSION: Thiamine supplementation was not provided to almost half of all patients with AUD, raising a quality-of-care issue for this cohort. Supplementation was numerically less frequent in patients with septic shock, DKA, or TBI than in those with alcohol withdrawal. These data will be important for the design of quality improvement studies in critically ill patients with AUD. PRIMARY FUNDING SOURCE: National Institutes of Health.

Psychophysiologic symptom relief therapy for chronic back pain: a pilot randomized controlled trial.

INTRODUCTION: Chronic back pain is the leading cause of disability in the United States. Based on the hypothesis that nonspecific back pain may be rooted in a psychophysiologic etiology, we propose a new approach to chronic back pain. OBJECTIVES: A pilot study was conducted to assess whether psychophysiologic symptom relief therapy (PSRT) can reduce disability and back pain bothersomeness for patients with chronic back pain. METHODS: This was a three-armed, randomized trial for adults with nonspecific chronic back pain that compared PSRT with usual care and an active comparator (mindfulness-based stress reduction [MBSR]). Psychophysiologic symptom relief therapy-randomized participants received a 12-week (36 hours) course based on the psychophysiological model of pain. All groups were administered validated questionnaires at baseline and at 4, 8, 13, and 26 weeks. The primary outcome was the reduction in pain disability measured by the Roland-Morris Disability Questionnaire. RESULTS: The mean Roland-Morris Disability Questionnaire score for the PSRT group (n = 11) decreased from 9.5 (±4.3 SDs) to 3.3 (±5.1) after 26 weeks which was statistically significant compared with both MBSR (n = 12) (P = 0.04) and usual care (n = 12) (P = 0.03). Pain bothersomeness scores and pain-related anxiety decreased significantly over 26 weeks in PSRT compared with MBSR and usual care (data in manuscript). At 26 weeks, 63.6% of the PSRT arm reported being pain free (0/10 pain) compared with 25.0% and 16.7% in MBSR and usual care arms, respectively. Psychophysiologic symptom relief therapy attendance was 76%, and there was 100% follow-up of all groups. CONCLUSION: Psychophysiologic symptom relief therapy is a feasible and potentially highly beneficial treatment for patients with nonspecific back pain.

Comparison between Patients Hospitalized with Influenza and COVID-19 at a Tertiary Care Center.

BACKGROUND: Widespread reports suggest the characteristics and disease course of coronavirus disease 2019 (COVID-19) and influenza differ, yet detailed comparisons of their clinical manifestations are lacking. OBJECTIVE: Comparison of the epidemiology and clinical characteristics of COVID-19 patients during the pandemic with those of influenza patients in previous influenza seasons at the same hospital DESIGN: Admission rates, clinical measurements, and clinical outcomes from confirmed COVID-19 cases between March 1 and April 30, 2020, were compared with those from confirmed influenza cases in the previous five influenza seasons (8 months each) beginning September 1, 2014. SETTING: Large tertiary care teaching hospital in Boston, MA PARTICIPANTS: Laboratory-confirmed COVID-19 and influenza inpatients MEASUREMENTS: Patient demographics and medical history, mortality, incidence and duration of mechanical ventilation, incidences of vasopressor support and renal replacement therapy, and hospital and intensive care admissions. RESULTS: Data was abstracted from medical records of 1052 influenza patients and 582 COVID-19 patients. An average of 210 hospital admissions for influenza occurred per 8-month season compared to 582 COVID-19 admissions over 2 months. The median weekly number of COVID-19 patients requiring mechanical ventilation was 17 (IQR: 4, 34) compared to a weekly median of 1 (IQR: 0, 2) influenza patient (p=0.001). COVID-19 patients were significantly more likely to require mechanical ventilation (31% vs 8%) and had significantly higher mortality (20% vs. 3%; p<0.001 for all). Relatively more COVID-19 patients on mechanical ventilation lacked pre-existing conditions compared with mechanically ventilated influenza patients (25% vs 4%, p<0.001). Pneumonia/ARDS secondary to the virus was the predominant cause of mechanical ventilation in COVID-19 patients (94%) as opposed to influenza (56%). LIMITATION: This is a single-center study which could limit generalization. CONCLUSION: COVID-19 resulted in more weekly hospitalizations, higher morbidity, and higher mortality than influenza at the same hospital.

Residual Enoxaparin Activity, Anti-Xa Levels, and Concerns About the American Society of Regional Anesthesia and Pain Medicine Anticoagulation Guidelines.

Currently, the American Society of Regional Anesthesia and Pain Medicine (ASRA) anticoagulation guidelines recommend that before the performance of a neuraxial procedure a minimum of 24 hours should elapse following a treatment dose of enoxaparin (1 mg/kg twice daily or 1.5 mg/kg once daily). The guidelines have since their inception also consistently recommended against the routine use of anti-Xa level monitoring for patients receiving enoxaparin. However, we noted in our clinical practice that anti-Xa levels were frequently still elevated despite patients meeting the time-based recommendation for treatment dose enoxaparin. To further investigate the possibility that residual anticoagulant activity may persist longer than 24 hours after a treatment dose of enoxaparin, we assessed anti-Xa level activity in patients presenting for elective surgery. Despite nearly universal compliance with ASRA's anticoagulation guidelines (1 sample was drawn at 23.25 hours), anti-Xa activity was found to be elevated in 11 of 19 patients. While 10 patients had an anti-Xa level within the peak prophylactic range (0.2-0.5 IU/mL), 1 patient's level was found to still be in the peak therapeutic range (0.5-1.0 IU/mL). These findings suggest that significant anticoagulant activity may persist longer than previously appreciated after the last treatment dose of enoxaparin and that the current time-based ASRA recommendation may not be conservative enough. Further research is needed to delineate the level of anti-Xa activity below which it is likely safe to proceed with a neuraxial procedure, but it may be time to reconsider the utility of anti-Xa level monitoring when it is available.

Proper Controls to Electrochemically Evaluate Carotenoids using ß-Cyclodextrin Modified Surfaces.

We initially tested the electrochemical activity of beta-carotene and lutein at unmodified glassy carbon electrodes. We found good sensitivity (1 nA/µM) at high, micromolar concentrations, but serum levels are at nanomolar concentrations. To enhance the electrochemical activity, we modified the sensor surface with ß-cyclodextrin, which has a hydrophobic core. Our goal was that the beta-carotene will be attracted to the ß-cyclodextrin core, increasing surface interaction and sensitivity. Instead we saw a decrease in electrochemical activity. Further investigation with a methylene blue mediator indicated two results. First, it is unlikely the beta-carotene strongly interacts with the ß-cyclodextrin surface. And, second, the presence of a co-solvent or surfactant can greatly disrupt the surface ß-cyclodextrin activity.

Residual and Dynamic Range of Retinal Nerve Fiber Layer Thickness in Glaucoma: Comparison of Three OCT Platforms.

PURPOSE: To estimate visual field (VF) sensitivity at which retinal nerve fiber layer (RNFL) thinning reaches the measurement floor and at which RNFL stops thinning (change points), the dynamic range of RNFL thickness, and the number of steps from normal to RNFL floor among three optical coherence tomography (OCT) devices. METHODS: Glaucomatous patients (n = 58) and healthy subjects (n = 55-60) prospectively underwent VF testing and RNFL thickness measurement with Cirrus, Spectralis, and RTVue. Change points and corresponding RNFL thicknesses were estimated with simple linear regression (SLR) and Bayesian change point (BCP) analyses. The dynamic range and number of steps to RNFL floor were determined. RESULTS: The average VF change points and corresponding residual thickness at the time RNFL stopped thinning were -22.2 dB and 57.0 µm (Cirrus), -25.3 dB and 49.2 µm (Spectralis), and -24.6 dB and 64.7 µm (RTVue). The RNFL dynamic ranges derived from SLR values were wider on Spectralis (52.6 µm) than on Cirrus (35.4 µm) and RTVue (35.5 µm); the corresponding number of steps to reach the RNFL floor were 9.0 on Cirrus, 10.6 on Spectralis, and 8.3 on RTVue. CONCLUSIONS: The relative VF sensitivity at which average RNFL thickness reaches the measurement floor, the residual layer thickness, and RNFL dynamic measurement range differ among the three devices. However, the number of steps from normal to the RNFL thickness floor is comparable.

ADAM-9 is an insulin-like growth factor binding protein-5 protease produced and secreted by human osteoblasts.

IGF binding protein-5 (BP-5) is an important bone formation regulator. Therefore, elucidation of the identity of IGF binding protein-5 (BP-5) protease produced by osteoblasts is important for our understanding of the molecular pathways that control the action of BP-5. In this regard, BP-5 protease purified by various chromatographic steps from a conditioned medium of U2 human osteosarcoma cells migrated as a single major band, which comigrated with the protease activity in native PAGE and yielded multiple bands in SDS-PAGE under reducing conditions. N-Terminal sequencing of these bands revealed that three of the bands yielded amino acid sequences that were identical to that of alpha2 macroglobulin (alpha2M). Although alpha2M was produced by human osteoblasts (OBs), it was not found to be a BP-5 protease. Because alpha2M had been shown to complex with ADAM proteases and because ADAM-12 was found to cleave BP-3 and BP-5, we evaluated if one of the members of ADAM family was the BP-5 protease. On the basis of the findings that (1) purified preparations of BP-5 protease from U2 cell CM contained ADAM-9, (2) ADAM-9 is produced and secreted in high abundance by various human OB cell types, (3) purified ADAM-9 cleaved BP-5 effectively while it did not cleave other IGFBPs or did so with less potency, and (4) purified ADAM-9 bound to alpha2M, we conclude that ADAM-9 is a BP-5 protease produced by human OBs.

Insulin-like growth factor-binding protein 5 (IGFBP-5) interacts with a four and a half LIM protein 2 (FHL2).

Recent studies using insulin-like growth factor I (IGF-I) knockout mice demonstrate that IGF-binding protein (IGFBP)-5, an important bone formation regulator, itself is a growth factor with cellular effects not dependent on IGFs. Because IGFBP-5 contains a nuclear localization sequence that mediates transport of IGFBP-5 into the nucleus, we propose that IGFBP-5 interacts with nuclear proteins to affect transcription of genes involved in bone formation. We therefore undertook studies to identify proteins that bind to IGFBP-5 using IGFBP-5 as bait in a yeast two-hybrid screen of a U2 human osteosarcoma cDNA library. Five related clones that interacted strongly with the bait corresponded to the FHL2 gene, which contains four and a half LIM domains. Co-immunoprecipitation studies with lysates from U2 cells overexpressing FHL2 and IGFBP-5 confirmed that interaction between IGFBP-5 and FHL2 occurs in whole cells. In vitro interaction studies revealed that purified FHL2 interacted with IGFBP-5 but not with IGFBP-3, -4, or -6. Northern blot analysis showed that FHL2 was strongly expressed in human osteoblasts. Nuclear localization of both FHL2 and IGFBP-5 was evident from Western immunoblot analysis and immunofluorescence. The role of FHL2 as an intracellular mediator of the effects of IGFBP-5 and other osteoregulatory agents in osteoblasts will need to be verified in future studies.